Systems, methods and devices for a skull/brain interface

ABSTRACT

Methods, devices, and systems induce neuromodulation by focusing a source of stimulation through a skull/brain interface in the form of an aperture formed in the skull, a naturally occurring fenestration in the skull, or a transcranial channel. Methods, devices, and systems identify where to locate skull/brain interfaces, accessories that can be used with the interfaces, and features for controlling stimulation delivered through the interfaces. Multiple indications for the skull/brain interfaces include diagnosis and treatment of neurological disorders and conditions such as epilepsy, movement disorders, depression, Alzheimer&#39;s disease, autism, coma, and pain.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.16/218,373 to Wingeier, et al., entitled “Systems, Methods and Devicesfor a Skull/Brain Interface” and filed Dec. 12, 2018, which is acontinuation of U.S. application Ser. No. 15/225,741 to Wingeier, etal., entitled “Systems, Methods and Devices for a Skull/Brain Interface”and filed Aug. 1, 2016, now U.S. Pat. No. 10,188,860, which is acontinuation of U.S. application Ser. No. 14/223,478 to Wingeier, etal., entitled “Systems, Methods and Devices for a Skull/Brain Interface”and filed Mar. 24, 2014, now U.S. Pat. No. 9,440,064, which is adivisional of U.S. application Ser. No 12/243,733 to Wingeier, et al.,entitled “Systems, Methods and Devices for a Skull/Brain Interface” andfiled Oct. 1, 2008, now abandoned, which is a continuation-in-part ofand claims priority to pending U.S. application Ser. No. 11/929,801 toWingeier, et al., entitled “Systems, Methods and Devices for aSkull/Brain Interface” and filed Oct. 30, 2007, now U.S. Pat. No.9,179,850, each of which is incorporated herein by reference in itsentirety.

BACKGROUND Technical Field

The inventions disclosed herein are directed to systems, devices andmethods for establishing an interface through the thickness of the skullfor purposes such as delivering some form of neuromodulation (e.g.,electrical or optical stimulation, pharmaceutical stimulation or thermal(e.g., cooling or delivering ultrasound to the brain)) to targetedstructures in the brain in a controlled manner to modulate neuralactivity, and detecting signals generated by neurons in targetedstructures in the brain.

Background

Much research and clinical development activity is ongoing in the areaof using various forms of neuromodulation to affect the brain (e.g., todiagnose or treat a neurological disorder). There is also continuinginterest in improving the quality or fidelity with which signals can besensed or measured from the brain, especially in electroencephalographybut also with respect to measurements associated with things such asimpedance plethysmography, tomography, and optical imaging.

Electrical Stimulation

Neuronal activity can be measured as electrical signals. This activityalso can be modulated (e.g., to inhibit undesired activity by blockingthe action potentials that allow the neurons to “fire”, to increase ordecrease the excitability of a group of neurons, or to cause neurons tofire) by inducing an electric field in neural tissue, or stated anotherway, in the vicinity of a group of neurons.

One way of inducing an electric field is by conducting electricity tothe neural tissue through an electrode-to-tissue interface (ETI).Implantable and partially implantable systems are known which candeliver neuromodulation in this manner. For example, U.S. Pat. No.6,016,449 to FISCHELL et al., issued Jan. 18, 2000 for a “System forTreatment of Neurological Disorders” describes an implantableneurostimulation system which, through electrodes implanted on thesurface of or in the brain, detects signals (referred to aselectrocortical signals or “ECoG”s because they are measured directly atthe brain as opposed to through the skull, as is the case with aconventional electroencephalogram). The system can be configured sothat, when the neurostimulator detects certain types of activity in theECoGs, e.g., activity that is believed to be associated with a seizureor to be a precursor of a seizure, it will deliver electricalstimulation to targeted areas of the brain in the form of various typesof electrical waveforms, with the intention of eliminating seizureactivity and/or reducing the severity of the seizures.

The types of waveforms that can be delivered through anelectrode-to-tissue interface are limited inasmuch as the charge densityper phase has to be low enough to be considered safe and chargebalancing must occur. More specifically, in a conventional electrode,current is carried by movement of electrons within the electrode,typically a metallic substance. However in an aqueous, non-metallicenvironment such as the human body, current is created largely by themovement of ions (charged particles) within the environment. In orderfor electrical charge delivered by an electrode to pass into and affectthe surrounding tissue, the electric current flowing through theelectrode must be converted into ion movement in the tissue.

This conversion can happen in two ways, by virtue of capacitance orelectrochemical reactions.

More specifically, an electrode interface, such as anelectrode-to-tissue interface, is capacitive; that is, it can store asmall amount of electrical charge without any actual transfer of chargefrom electrode to tissue. Consider two pipes attached end-to-end with arubber membrane separating them. A small amount of flow in one pipe canballoon out the membrane, and, as long as the amount of flow is notgreat enough to burst the membrane, the net flow of current istransferred to the second pipe. If the flow is then repeatedly reversed(the analogy here being to alternating current), the system appears asif it were one single pipe with no barrier. This occurs, electrically,when small amounts of charge are delivered in a biphasic pulse; theleading phase stores charge in one direction, and the trailing phaseremoves charge to restore the balance.

If the electrical charge to be passed exceeds the capacitive limit ofthe electrode-to-tissue interface, then the only remaining way totransfer charge is by electrochemical reactions occurring at theelectrode-to-tissue interface. The precise nature of the reactions thatoccur depend on the voltage across the ETI, but the reactions are almostalways undesirable because they can result in, for example, hydrogenions, hydrogen gas, hydroxide ions, oxygen gas, and other possibly toxicsubstances being introduced into the tissue, and denaturation ofproteins already present in the tissue. The reactions can also result inerosion of the electrode and distribution of the electrode material intothe surrounding tissue. Current passed in this way is often referred toas Faradaic current. For the sake of completeness, it is noted that inpractice, a small amount of reaction product can be absorbed by areversed electrochemical reaction on the trailing phase of a biphasicstimulus. This is known as pseudocapacitance. The actual safe charge perphase of a stimulation system (i.e., the amount of charge per phase thatdoes not result in undesirable electrochemical changes in the tissueover time) thus is governed by the sum of the actual capacitance and thepseudocapacitance.

In view of the foregoing, a goal associated with use of electricalneurostimulation systems using implanted electrodes is to keep thecharge passed per phase within the capacitive limit of the ETI. Themagnitude of this limit is key to safety of electrical neurostimulation,and has been characterized for some materials from which electrodes arecommonly fabricated. Platinum, for example, yields a theoretical chargestorage capacity of 200 μC/cm² (micro coulombs per square centimeter)and a practical charge storage capacity of 50 μC/cm². Oxide materialssuch as iridium oxide may reversibly store more than 1000 μC/cm². Thesecharge densities are more than sufficient for pulsatile or highfrequency stimulation in most cases. By comparison, a typical deep brainstimulus of 3 mA for a 90 μS pulse width on a 5.7 mm² electrode passes 5μC/cm². On the other hand, low frequency, non-pulsatile electricalstimulation is constrained in most cases by these limits. For instance,a 1 Hz sinusoid delivered at 1 mA peak-to-peak on a 5.7 mm² electrodepasses 2800 μC/cm² per phase. (GRILL, W. M., “Safety Considerations forDeep Brain Stimulation: Review and Analysis,” Expert Rev. Med. Devices(2005), 2(4): 409-420 and MERRILL, D. R., et al., “ElectricalStimulation of Excitable Tissue: Design of Efficacious and SafeProtocols,” J. Neurosci. Meth. (2005), 141: 171-198.)

Accordingly, the waveforms used in electrical stimulation deliveredthrough an electrode-to-tissue interface are those which can bothmaintain charge balancing and either avoid or reverse anyelectrochemical reactions at the ETI as they begin to occur. Stimulationusing waveforms that satisfy these criteria will be referred to hereinas “pulsatile stimulation” or “AC stimulation.” Examples of thesewaveforms are biphasic pulsatile waveforms (as are commonly used fordeep brain and cortical neurostimulation) (see MERRILL et al.,“Electrical Stimulation of Excitable Tissue: Design of Efficacious andSafe Protocols,” J. Neurosci. Meth. (2005) 141: 171-198), and sinusoidalor near-sinusoidal waveforms at high frequencies such as 100 Hz andabove.

There are also neuromodulation techniques which rely only upon anexternal stimulation source and which are believed to modulate neuralactivity by inducing a current in neural tissue. One of these techniquesis Transcranial Electrical Stimulation or “TES.” TES involves applyingelectrodes to the scalp which, when provided with an electrical signal,result in some current flow in the brain which in turn has the effect ofmodulating the activity of groups of neurons. TES is usually not apreferred approach to treating a disorder or other condition of apatient, because most of the current from the stimulation flows throughthe scalp, from electrode to electrode, rather than into the brain, andthis current flow causes pain and discomfort, due to stimulation ofnerves in the scalp, and contraction of the scalp muscles. It has beenused as a form of electroconvulsive therapy (ECT) with the patient underanesthesia, to treat depression.

Transcranial Direct Current Stimulation (tDCS) is another technique tomodulate the electrical activity of neurons. In this technique, weakelectrical currents (on the order of 0.1 to two milliamps) are appliedthrough electrodes placed externally on the scalp, with conduction tothe scalp facilitated by a saline-saturated sponge or a layer ofconductive gel. The currents, and the resulting static DC fields, arebelieved to alter the firing rates of neurons. tDCS is beinginvestigated for use in treatment of several conditions; for example,major depression. For example, in one reported double-blind study,anodal tDCS was applied to the left dorso-lateral prefrontal cortex andwas observed to improve mood in 40 patients when compared to both anodaltDCS applied to the occipital cortex (believed to be unrelated todepression) and sham stimulation. (See BOGGIO, P. S., et al., “ARandomized, Double-Blind Clinical Trial on the Efficacy of CorticalDirect Current Stimulation for the Treatment of Major Depression,” Int.J. Neuropsychopharmacol (2007) 11, 1-6. Another study has reportedimproved go-no-go task performance in depressed patients using a similarprotocol. (See BOGGIO, P. S., et al., “Go-No-Go Task PerformanceImprovement after Anodal Transcranial DC Stimulation of the LeftDorsoLateral Prefrontal Cortex in Major Depression,” J. Affect Disord.(2006) 101(1-3): 91-8.

tDCS also has been used experimentally to treat a variety ofneurological disorders, as well as in experiments designed to study andenhance cognitive function in normal human subjects. Most studies haveconcluded that tDCS has a mild neuromodulatory effect, often of clinicalvalue and often lasting beyond the immediate stimulation period. Ascientific review of experimental, human clinical use of tDCS isprovided in FREGNI, F., et al., “Technology Insight: Noninvasive BrainStimulation in Neurology—Perspectives on the Therapeutic Potential ofrTMS and tDCS,” Nat. Clin. Pract. Neurol. (2007) 3(7): 383-93). Thereare some articles in the popular press on the subject as well, such asTRIVEDI, B., “Electrify Your Mind—Literally,” New Scientist, 15 Apr.2006, and KENNEDY, P., “Can A Jolt From A Nine-Volt Battery Make YouSmarter? Happier? Medical Researchers Revive A Discarded Technology andSet the Stage for the ‘Brain Pod’,” The Phoenix, 7 Feb. 2007.

For example, stroke rehabilitation using tDCS, particularlyrehabilitation for strokes that caused some type of motor deficit, hasbeen studied by several groups. Anodal tDCS, applied to the area of anischemic lesion, improved standard measures of motor function in asham-controlled group of six patients with mild motor deficit (asdisclosed in HUMMEL, F., et al., “Effects Of Non-Invasive CorticalStimulation On Skilled Motor Function In Chronic Stroke,” Brain (2005)128:490-00) and in a group of eleven patients with severe motor deficit(as disclosed in HUMMEL, F. et al., “Effects of Brain Polarization OnReaction Times And Pinch Force In Chronic Stroke,” BMC Neuroscience(2006) 7:73.) In this and other applications, anodal tDCS is believed tobe excitatory, increasing cortical excitability and enhancing neuralplasticity in the stimulated region. The effect is believed to lastsomewhat beyond the actual stimulation session.

Further, application of cathodal tDCS to the area contralateral to anischemic lesion, in addition to anodic tDCS to the lesion area, has beenobserved to similarly improve motor function in six patients with mildto moderate motor deficit (as disclosed in FREGNI, F., et al.,“Transcranial Direct Current Stimulation Of The Unaffected Hemisphere InStroke Patients,” Neuroreport (2005) 16: 1551-1555.) In this and otherapplications, cathodal tDCS is believed to be inhibitory, decreasingcortical excitability and in particular decreasing output of thestimulated region.

Cathodal tDCS, applied over an epileptic cortex, has been shown in atleast one report to reduce the number of epileptiform dischargesobserved within 30 days after stimulation (as disclosed in FREGNI, F.,et al., “A Controlled Clinical Trial Of Cathodal DC Polarization InPatients With Refractory Epilepsy,” Epilepsia (2006) 47(2): 335-342). Atrend toward reduced seizure frequency, i.e., not reaching the level ofp=0.05 significance, was also observed after cathodal tDCS. It was notedin this study that anodal tDCS, applied over the contralateral,non-epileptic cortex, did not cause increased epileptiform discharges. Asimilar treatment currently is the focus of a trial sponsored by theNational Institute of Neurological Disorders and Stroke for 56 patients(see “Anticonvulsive Effects of Transcranial DC Stimulation inPharmacoresistant Focal Epilepsy,” NIH Protocol No. 06-N-0187 (2006).)

Neurostimulation using pulsatile waveforms applied to the motor cortexhas been used for treating chronic pain, especially for pain ofneuropathic or central origin. Using tDCS to treat such pain has alsobeen reported. In one study of 17 patients (as disclosed in FREGNI, F.,et al., “A Sham-Controlled, Phase II Trial Of Transcranial DirectCurrent Stimulation For The Treatment Of Central Pain In TraumaticSpinal Cord Injury,” Pain (2006) 122: 197-209), anodal tDCS over theprimary motor cortex was shown to significantly reduce pain due tofibromyalgia when compared to both sham stimulation and anodalstimulation of the dorso-lateral prefrontal cortex (DLPFC, an area ofcortex which is thought to be unrelated to the condition of centralpain).

Some are investigating using tDCS for treatment of the movement disorderParkinson's disease. One report suggests beneficial effects onmotor-task scores and motor-evoked potentials in 17 Parkinsonianpatients (FREGNI, et. al., “Noninvasive Cortical Stimulation withTranscranial Direct Current Stimulation in Parkinson's Disease,” Mov.Disord. (2006) 21: 1693-1702.

Still another promising area of tDCS research involves cognitiveenhancement in normal human subjects. tDCS administered during slow-wavesleep has been observed to increase retention of memorized word pairssignificantly, in comparison with both sham stimulation and tDCSadministered in those who are awake. (See MARSHALL, L., et al.,“Transcranial Direct Current Stimulation during Sleep ImprovesDeclarative Memory,” J. Neurosci. (2004) 24 (44): 9985-9992, ascorrected in J. Neurosci. 25(2).)

Fregni et al. also observed enhanced performance with a working memorytask, in 15 subjects, with anodic tDCS applied over the leftdorso-lateral prefrontal cortex. (FREGNI, F., et al., “AnodalTranscranial Direct Current Stimulation Of Prefrontal Cortex EnhancesWorking Memory,” Exp. Brain Res. (2005) 166(1): 23-30.) This enhancedperformance was contrasted to cathodic stimulation of the left DLPFC,which had no effect, and anodic stimulation of the primary motor cortex,which also had no effect and which is believed to be an area of cortexirrelevant to working memory. In another study, Marshall et al.identified significant slowing of reaction time in 12 subjects withbilateral frontal tDCS, during a working memory task (MARSHALL et al.,“Bifrontal Transcranial Direct Current Stimulation Slows Reaction TimeIn A Working Memory Task,” BMC Neuroscience (2005) 6:23.)

Administration of anodal tDCS over left prefrontal cortex has also beenshown to significantly increase verbal fluency in contrast with cathodaltDCS, which resulted in a mild decrease in fluency. (IYER, M. B., etal., “Safety and Cognitive Effect of Frontal DC Brain Polarization inHealthy Individuals,” Neurology (2005) 64(5): 872-5.)

In addition, one study suggests that alcohol craving can be decreasedusing anodic-left/cathodic-right and anodic-right/cathodic-left tDCS ofthe dorso-lateral prefrontal cortex. (BOGGIO, P. S., “Prefrontal CortexModulation Using Transcranial DC Stimulation Reduces Alcohol Craving: ADouble Blind, Sham-Controlled Study,” Drug Alcohol Depend, 17 Jul.2007.) The effect was demonstrated in 13 subjects to be significant incomparison to sham stimulation, regardless of tDCS polarity.

Some of the difficulties facing researchers investigating variousapplications of tDCS relate to the ability to focus the stimulation ontarget areas of the brain and the ability to accurately or repeatedlylocate the scalp electrodes to provide the desired stimulation.

Modeling of current and electrical field distribution in tDCS shows thatelectrical fields sufficient for neuromodulation are widely distributedthroughout the brain. (See LU, M, et al., “Comparison of Maximum InducedCurrent and Electric Field from Transcranial Direct Current and MagneticStimulation of A Human Head Model,” PIERS Online 3(2) (2007) 179-183.)

This is significant, since most applications or potential applicationsof tDCS will require stimulation of a defined cortical structure, suchas the primary motor cortex. Even those applications which involveproviding diffuse stimulation of a larger structure, such as thedorsolateral prefrontal cortex, will likely target that structure only,such that stimulation of nearby structures would not be optimum.

Another issue in tDCS may be unfocused and/or undesired stimulation dueto the reference electrode. While such stimulation may be mitigatedsomewhat by placing the reference electrode away from the patient'shead, such placement may raise other issues. For example, placing thereference electrode elsewhere may result in unintended neuromodulationof the brain stem, due to the diffuse nature of the current flow. (SeeNITSCHE, M. A., et al., “Modulation of Cortical Excitability by WeakDirect Current Stimulation—Technical, Safety and Functional Aspects,”Supp. Clin. Neurophysiol. (2003) 56: 255-76.)

There have been several attempts to address the focality issue withtDCS. It has been shown that smaller stimulating electrodes and largerreference electrodes contribute to focal stimulation. (See NITSCHE, M.A., et al., “Shaping The Effects Of Transcranial Direct CurrentStimulation Of The Human Motor Cortex,” J. Neurophysiol. (2007)97:3109-3117.) Concentric ring electrodes have also been proposed, andused in an animal model, to provide more focused transcranial DCstimulation and to reduce reference electrode effects. (See BESIO, W.G., et al., “Effects Of Noninvasive Transcutaneous ElectricalStimulation Via Concentric Ring Electrodes On Pilocarpine-Induced StatusEpilepticus In Rats,” Epilepsia, 25 Jul. 2007.) Accurate mapping ofelectrical properties of the head, and finite element modeling of tDCScurrent flow, has also been proposed as a way to increase focality oftDCS. (U.S. Patent Application Publication No. 2007/0043268, “GuidedElectrical Transcranial Stimulation (GETS) Technique,” to RUSSELL, Feb.22, 2007.) However, all of these techniques are still fundamentallylimited by current preferentially flowing through the scalp, andblurring of the intracranial neuromodulatory field due to high skullresistivity. This is analogous to the situation in EEG; resolution isincrementally improved by using more electrodes but a fundamental limitis soon reached, with diminishing returns after about 2.5 cminter-electrode spacing, due to blurring of the signal by interveningtissue. (See SRINIVASAN, R., “Methods To Improve The Spatial ResolutionOf EEG,” Int. J. Bioelectromagnetism (1999) 1(1):102-111.)

Other techniques for applying electrical stimulation to the brain areunder investigation that use waveforms (as opposed to direct current)which do not meet the definition of “pulsatile” or “AC” set forth above,i.e., the waveforms are not suitable for maintaining charge balance andfor minimizing undesirable electrochemical reactions at theelectrode-to-tissue interface. Stimulation using these waveforms will bereferred to in this disclosure as “non-pulsatile stimulation” or“near-DC stimulation.” Examples of these waveforms are large amplitudeor slowly varying oscillatory waveforms and low frequency sinusoidalwaveforms. The nature of these waveforms is such that they exceed thelimits of charge density per phase that are deemed safe at theelectrode-to-tissue interface or they do not permit charge balancing tobe maintained when the waveforms are delivered. Low frequency sinusoidalstimulation has shown some efficacy in animal models of epilepsy. (SeeGOODMAN, J. H., et al., “Low-Frequency Sine Wave Stimulation DecreasesSeizure Frequency In Amygdala-Kindled Rats,” Epilepsia (2002) 43(supp7): 10, and GOODMAN, J. H., et al., “Preemptive Low-FrequencyStimulation Decreases The Incidence Of Amygdala-Kindled Seizures,”Epilepsia (2005) 46(1): 1-7.)

In summary, then, the sources for electrical stimulation discussed abovecan be conveniently (for the purposes of this disclosure) grouped intothese categories: (1) pulsatile or AC stimulation; (2) DC stimulation;and (3) non-pulsatile and near-DC stimulation. Applying electricalstimulation to modulate neural activity through an electrode-to-tissueinterface typically requires invasive surgery to implant the electrodes,e.g., deep in the brain, on the cortex (cortical electrodes), or on thedura (epidural electrodes). The type of stimulation that can bedelivered through the electrodes is limited, as a practical matter, topulsatile or AC stimulation, because the waveforms used have anacceptable charge-density-per-phase and maintain charge balancing whendelivered. Non-pulsatile or near-DC stimulation and direct currentstimulation should not be applied through an implantedelectrode-to-tissue interface because of unacceptable charge densitiesand the inability to maintain charge balancing during delivery. Withoutthe implanted electrode-to-tissue interface, however, focusing thestimulation where it is desired to modulate neural activity isdifficult, since the resistance of the skull tends to diffuse theelectrical fields so that they are widely distributed throughout thebrain. In addition, in tDCS, locating the scalp electrodes inaccuratelycan lead to errors in delivery of the stimulation, or in interpretingthe results.

Magnetic Stimulation

Another technique for neuromodulation that is being explored is referredto as Transcranial Magnetic Stimulation or “TMS.” TMS is thought toinduce eddy currents in the surface of the brain that stimulate a groupof neurons. In this technique, the coil of a magnet is held against thehead and energized by rapidly discharging a capacitor, which creates arapidly changing current in the coil windings. This rapidly changingcurrent sets up a magnetic field at a right angle to the plane of thecoil. The magnetic field goes through the skin and skull to the brainand induces a current tangential to the skull. This current influencesthe electrical activity of the neurons. TMS can be applied on asingle-pulse or paired-pulse basis, or repetitively (rTMS). TMS is notassociated with the often high level of discomfort that accompanies TES.However, TMS is not favored in surgical environments because of thedifficulties presented by having multiple metal objects in theenvironment. In addition, when used in any environment, TMS equipment istypically bulky to manipulate and consumes a lot of power. Also, thestimulation parameters in TMS tend to be less consistent than those thatcan be achieved with other types of electrical stimulation. TMS is underinvestigation for treatment of migraine headaches, amblyopia, anddepression, among other neurological disorders and conditions.

Neuromodulation Using lontophoresis

Lontophoresis refers to the techniques of moving an ionically-chargedsubstance into and through tissue by electromotive force. The basictechnique is well known, and has been used for delivering suchbiologically active agents (also known as bioactive agents) asanti-inflammatory medications, and topical anesthetics. Bioactive agentsintended to affect neural tissue also can be delivered vialontophoresis. These agents may include but are not limited toglutamate, acetylcholine, valproate, aspartate, and gamma aminobutyrate. Reverse lontophoresis (i.e., extraction of substances, usuallyfor measurement) also is a well known technique in some applications asglucose monitoring. (See, e.g., RHEE, S. Y., et al., “ClinicalExperience of an lontophoresis Based Glucose Monitoring System,” J.Korean Med. Sci. (2007) 22:70-3.)

Jacobsen, et al. describe early improvements for safety and comfort oflontophoresis and applications such as transdermal delivery ofpilocarpine for diagnosis of cystic fibrosis, and transdermal deliveryof anesthetic substances. U.S. Pat. No. 4,141,359 to JACOBSEN et al. for“Epidermal lontophoresis Device,” issued Feb. 27, 1979.

Using waveforms other than DC waveforms in iontophoresis are also known.For example, Liss et al., describes a three-component modulatedwaveform, reviews other iontophoretic waveforms, and presents resultsfor iontophoretic diffusion of the bioactive substancesadrenocorticotropic hormone (ACTH), cortisol, beta endorphin, andserotonin. U.S. Pat. No. 5,421,817 to LISS et al. for “Non-IntrusiveAnalgesic NeuroAugmentive and Iontophoretic Delivery Apparatus andManagement System,” issued Jun. 6, 1995.

Lontophoresis also has been recognized as a promising avenue fordelivery of substances into the brain. Lerner has proposed iontophoreticadministration of pharmaceuticals into the brain tissue via transnasalor transocular paths. U.S. Pat. No. 6,410,046 to LERNER for“Administering Pharmaceuticals to the Mammalian Central Nervous System,”issued Jun. 25, 2002.

Lerner further has disclosed iontophoretic administration of bioactivesubstances to the central nervous system, using a source of bioactivesubstance that may be implanted at the brain surface. U.S. Pat. No.7,033,598 to LERNER for “Methods and Apparatus for Enhanced andControlled Delivery of a Biologically Active Agent into the CentralNervous System of a Mammal” issued Apr. 25, 2006. In addition, Abreu hasdisclosed iontophoretic delivery of substances via a naturally-occurringphysiologic “brain-temperature tunnel” or “BTT.” U.S. Pat. No. 7,187,960to ABREU for “Apparatus and Method for Measuring Biologic Parameters,”issued Mar. 6, 2007.

Stimulation Using Light

Techniques using light to modulate the activity of genetically modifiedneural tissue are well known. (See, e.g., DEISSEROTH, K., et al.,“Next-Generation Optical Technologies for Illuminating GeneticallyTargeted Brain Circuits,” J. Neurosci. (2006) 26(41): 10380-10386.)

Detecting Brain Activity

EEG

The electroencephalograph, or EEG, is a measurement of scalp potentialsresulting from the summed electrical contributions of many neurons. Poorspatial resolution of scalp EEG, due to spatial “blurring” of the signalby the relatively nonconductive skull, is a well known and wellunderstood issue; maximal scalp EEG resolution is on the order ofseveral centimeters, and decreasing inter-electrode spacing pastapproximately one centimeter yields virtually no improvement, since thesignals are already “blurred” by the time they reach the scalp.

Mathematical models such as the spline-Laplacian and dura imaging havebeen described for preferentially extracting high-spatial-frequencyinformation from the scalp EEG. (See, e.g., NUNEZ, P. L., et al., “ATheoretical and Experimental Study of High Resolution EEG Based onSurface Laplacian and Cortical Imaging,” Electroencephalogr. Clin.Neurophysiol. (1994) 90(1): 40-57; NUNEZ, P. L., et al., “Comparison OfHigh Resolution EEG Methods Having Different Theoretical Bases,” BrainTopogr. (1993) 5(4): 361-4.) These methods, however, still rely on asignal in which high-resolution spatial information is largely lost, anddue to fundamental mathematical issues, provide no way of unambiguouslyreconstructing the unblurred signal.

By placing electrodes directly on the cortex or dura, one can measureelectrical signals without experiencing the blurring caused by the skulland tissue that otherwise intervenes between the dura and the externalscalp surface. This electrocorticograph, or ECoG, contains significantlymore information at fine spatial scales than can be obtained withscalp-recorded signals. Obtaining ECoGs, however, requires invasivesurgery to place the electrodes on the cortex or dura. This method ofacquiring EEG is usually limited either to acute use or with achronically implanted device. In acute use, wires are typically run fromthe electrodes on the cortex through the skin to an external amplifier(e.g., for mapping epileptic foci over several days or weeks). Thistechnique is associated with a risk that the wires or electrodes willbecome dislodged and that the exposed area may become infected.

If a chronically implanted ECoG detector is used (such as that disclosedin U.S. Pat. No. 6,016,449 to FISCHELL et al., issued Jan. 18, 2000 fora “System for Treatment of Neurological Disorders”), the risk ofdislodgment and infection is lessened. However, to implant the deviceand the electrodes and associated leads is invasive and expensive. Powerand other design constraints may limit the extent to which implanteddevices can process ECoGs without external equipment.

Impedance Plethysmography and Tomography

Electrical impedance plethysmography is a well-known method forestimating the volume of an anatomical space by measuring electricalimpedance at various frequencies. It may be used to measure volumetricor density changes in neural and vascular tissue, such as changes inperfusion, that are associated or thought to be associated with changesin neural activity.

A map of brain plethysmographic changes may be reconstructed frommulti-channel scalp impedance measurements, a technique which is calledElectrical Impedance Tomography or “EIT”. (See, e.g., CLAY, M. T., etal., “Weighted Regularization in Electrical Impedance Tomography withApplications to Acute Cerebral Stroke,” IEEE Trans. Biomed. Eng. (2002)21(6): 629-637.) This plethysmographic signal, as measured on the scalp,is blurred in the same way that EEG signals are spatially blurred. Thus,reconstruction of even a crude tomographic image is both mathematicallycomplex and not highly accurate.

Optical Imaging and Tomography

Optical methods for measuring brain activity such as cerebral perfusionand cerebral hemodynamics are well known. Optical sensing currently hasbeen implemented for such things as direct optical recording ofintrinsic reflectance signals (ORIS) from the surface of the brain, andtranscranial optical tomography, which attempts to mathematicallyreverse scattering of light to skull and scalp tissue, in order toreconstruct a crude image of brain hemodynamics. (See, e.g., SUH, M., etal., “Blood volume and hemoglobin oxygenation response followingelectrical stimulation of human cortex,” NeuroImage (2006) 31:66-75, andHEBDEN, J. C., et al, “Three-dimensional optical tomography of thepremature infant brain,” Phys. Med. Biol. (2002) 47:4155-4166.)

Transferring Energy to and from the Brain

Investigations have suggested that removing energy from the brain mayhave application in eliminating or reducing the severity of neurologicaldisorders. For example, heat transfer has shown some promise as atechnique for neuromodulation. More specifically, heat transfer awayfrom a region of brain tissue (i.e., cooling) is known to reversiblydeactivate neural tissue (i.e., the deactivated tissue can bereactivated after the cooling source is withdrawn), and has been shownto suppress spontaneous epileptiform activity in humans. This phenomenonis believed to provide a potential treatment for focal epilepsy. (See,e.g., KARKAR, et al., “Focal Cooling Suppresses Spontaneous EpileptiformActivity without Changing the Cortical Motor Threshold,” Epilepsia(2002) 43(8): 932-935.) However, engineering of a practical implantablecooling device has proven non-trivial. (See, e.g., ROTHMAN, et al.,“Local Cooling: A Therapy for Intractable NeoCortical Epilepsy,”Epilepsy Curr. (2003) 5(5): 153-56.) Thermoelectric Peltier devicesappear to offer promise, but are known to be relatively inefficient.Provision of adequate power, and safe disposal of the resulting heat,are practical design constraints that militate against an implantablecooling system.

Transcranial heat transfer has also been analyzed. (See, e.g.,SUKSTANSKII, A. L., et al., “An Analytical Model of TemperatureRegulation in Human Head,” J. Themr. Biol. (2004) 29:583-587.) Surfacehead cooling can be used during bypass surgery to induce hypothermia,improving low oxygen survivability and affording more time in which toaccomplish the bypass procedures. Similarly, the surface of the head canbe cooled to reduce inflammation or for other purposes. However, thecooling effect on the brain is usually nominal using this technique, andit is hard to focus, in any event, especially in the presence of normalblood flow.

High intensity focused ultrasound (“HIFU”) can ablate tissue deep in thebody. It has been used to create lesions in the heart to treat atrialfibrillation and to ablate fibroid tumors. Using HIFU to treat the brainmay be desirable insofar it is less invasive than open brain surgery,which may be complicated by neurological deficits, among other things.The skull, however, is a difficult barrier through which to deliverultrasound energy, because the skull bone has a strong defocusing effecton the externally applied energy. Sophisticated techniques are beinginvestigated to help overcome the ultrasound-scattering effect of bone,such as time-reversal mirrors (See, e.g., TANTER, M., et al., “TimeReversal for Ultrasonic Transcranial Surgery And Echographic Imaging,”Abstract, Acoustical Society of America J. (2005) Vol. 118; Issue 3, p.1941), although skull heating during delivery of the ultrasound stillpresents an obstacle to this type of treatment.

Skull/Brain Interfaces

There have been some methods and devices disclosed for providing aninterface through the skull to the brain as an alternative to, on theone hand, external stimulation sources or sensing electrodes and, on theother hand, implanted electrodes with associated implanted or partiallyimplanted equipment.

For example, Lowry et al. have proposed positioning adjustable lengthintracranial electrodes through the thickness of the skull under localanesthesia, wherein a distal surface or extension of the electrode isadapted to electrically contact a surface of the brain, such as the duramater, the cerebral cortex, or a deep brain structure. The electrode isthen electrically connected to a pulse generator to apply electricalneurostimulation. U.S. Patent Application Publication No. 2004/0102828,published May 27, 2004 to LOWRY et al. for “Methods and SystemsEmploying Intracranial Electrodes for Neurostimulation and/orElectroencephalography.” In one embodiment, Lowry et al. discloses usingan electrically conductive elastomer in an intracranial electrode, e.g.,a polymeric material filled with a suitable quantity of a conductivemetal powder. Lowry et al. also does not disclose using anything otherthan pulsatile stimulation from a pulse generator to generate electricalneurostimulation of structures in the brain. (See, e.g., U.S. PatentApplication Publication No. 2004/0102828 [0077].)

Lowry et al. have also proposed an intracranial electrode having a headand a shaft such that a proximal portion of the head is flush with theouter layer of the skull. U.S. Patent Application Publication No.2005/0075680, published Apr. 7, 2005 to LOWRY et al. for “Methods andSystems for Intracranial Neurostimulation and/or Sensing”. Lowry et al.also disclose an intracranial electrode with an “electrical energytransfer mechanism” or “ETM” that is placed externally adjacent apatient's scalp to couple electrical energy from a pulse generator to anintracranial electrode having a core using an electrically conductivematerial in conjunction with a conductive gel layer in an intracranialelectrode system. (See, e.g., U.S. Patent Application Publication No.2005/0075680 [0138]-[0141], FIGS. 34A & B and FIG. 39.)

Fowler et al. have proposed a method using an electrode implanted in apatient's skull to transfer stimulation signals (e.g., from a pulsegenerator) through the scalp to a target neural population. U.S. PatentApplication Publication No. 2006/0106430, published May 18, 2006 toFOWLER et al. for “Electrode Configurations for Reducing Invasivenessand/or Enhancing Neural Stimulation Efficacy, And Associated Methods.”

The Lowry et al. and Fowler et al. references disclose only skull/braininterfaces through which signals are delivered or sensed using metal asa conductor. In addition, the only form of stimulation deliverable byany of the devices disclosed in the Lowry et al. references is pulsatileelectrical stimulation.

SUMMARY

Before the present systems, devices and methods are described, it is tobe understood that this disclosure is not limited to the particularsystems, devices and methods described, as these may vary. It is also tobe understood that the terminology used in the description is for thepurpose of describing the particular versions or embodiments only, andis not intended to limit the scope.

It must also be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural references unlessthe context clearly dictates otherwise. Thus, for example, reference toa “transcranial channel” is a reference to one or more transcranialchannels and equivalents thereof known to those skilled in the art, andso forth. Unless defined otherwise, all technical and scientific termsused herein have the same meanings as commonly understood by one ofordinary skill in the art. Although any methods, materials, and devicessimilar or equivalent to those described herein can be used in thepractice or testing of embodiments, the preferred methods, materials,and devices are now described. All publications mentioned herein areincorporated by reference. Nothing herein is to be construed as anadmission that the embodiments described herein are not entitled toantedate such disclosure by virtue of prior invention.

Described herein is a system and method for providing an interfacethrough the skull to the brain of a patient. In the system and method,the interface can be used for delivering a form of neuromodulation tothe brain, including but not limited to thermal (e.g., cooling thebrain), electrical pulsatile or AC, DC, and non-pulsatile or near-DCstimulation, neuromodulation or treatment using iontophoresis, andoptical neuromodulation. In this embodiment, the system and methodincludes forming one or more apertures in the skull, or using one ormore fenestrations preexisting in the skull, that extend all the waythrough the thickness of the skull or partially through the thickness ofthe skull, and providing a source for the stimulation in the vicinity ofthe aperture(s) or fenestration(s).

In the system and method, the interface also can be used for conveyinginformation from the brain externally of the skull for externalmeasurement or processing, including but not limited to for anelectroencephalogram, for impedance plethysmography and associatedtomography, and for optical imaging and associated tomography. In thisembodiment, the system and method includes forming one or more aperturesin the skull, partially or all the way through the skull, or using oneor more fenestrations preexisting and/or naturally-occurring in theskull, and providing a means for sensing one or more parameters that isunderstood or believed to be characteristic of a state or physiologicalprocess of the brain.

Further described herein are systems, devices, and methods using one ormore transcranial channels to provide a skull/brain interface forfacilitating such things as the delivery of neuromodulation to thebrain, measuring signals from the brain, and cooling the brain.

In the system and method, complementary components and assemblies may beused to encourage or enhance conduction from an external source ofstimulation to the brain or to an external measuring or detection deviceor system from the brain. Such complementary components include a scalpelectrode pad and scalp electrode pad assembly.

The transcranial channel may be provided having an outer wall and aninterior cavity and may be constructed of an ion-permeable material inwhole or in part. The outer wall may be formed in whole or in part of asubstance that is not permeable to ions or the outer wall may be coatedor otherwise surrounded on the exterior with such a material.

The interior cavity may be open at both the proximal and distal endsthereof, such that when the channel is positioned in the skull, theinterior cavity is left to be filled by the body with one or more ofserum or tissue (e.g., fibrous tissue, or in-scalp growth). Thesesubstances are significantly more ion-permeable (and thusion-conductive) than the skull tissue removed when the channel isimplanted. Serum, especially, which may be expected to fill the cavitywell before any tissue ingrowth occurs, is a fluid containing ions,similar to cerebrospinal fluid (“CSF”), and thus is highly conductive toion flow.

The interior cavity may be fillable or filled or partially filled withan ion-permeable substance other than air, such as a saline solution, ahydrogel, a porous silicone, or a sponge; the matrix of this permeablesubstance may be infiltrated with a bioactive material such as anantiproliferative agent, for example atomic silver, bone morphogenicproteins, ciliary neurotrophic factor, ribavirin, sirolimus,mycophenolate, mofetil, azathioprine, paclitaxel, or cyclophosphamide,or a bactericidal and/or bacteriostatic agent, for example quinolone,fluoroquinolone, beta-lactam, aminoglycoside, penicillin, macrolide,monobactam, lincosamide, tetracycline, cephalosporin, lipopeptide,streptogramin, carbapenem, sulfonamide, aminoglycoside, oxalodinone,nitrofuran, ketolide, glycylcycline families of antibiotics, or silverions. Other types of bioactive agents may also be used.

In one variation, an end cap or cover, for example in the form of apermeable or semi-permeable membrane, may be provided at one or both ofthe proximal or distal ends of the channel.

The transcranial channel may be provided with an overall length that isdesigned to traverse the entire thickness of the skull or only a part ofthickness of the skull, e.g., 90% of the thickness of the skull.

In one variation, the length of the channel is about the same as theoverall width of the channel.

In another variation, the channel may be provided as a plug formed froman ion-permeable material.

Any of the channels, for example, the channel with the interior cavityor the channel in the form of a plug, may be provided with a taper fromthe proximal end to the distal end thereof.

In a still further variation, the overall width of the channel is muchgreater than the length of the channel. This variation further may bedesigned to fit in an aperture or naturally-occurring or otherwisepreexisting fenestration in the skull or over an aperture orfenestration in the skull.

In another variation, the transcranial channel may be provided with aplurality of inner lumens. The inner surface of the outer layer may reston the outer surface of the inner lumen or a gap may be provided betweenthe inner lumen and the outer layer. The outer layer may be formed usinga non ion-permeable material, such materials including but not limitedto metals, non-permeable silicone, and polymers such aspolyetheretherketones. This outer layer will help prevent conductioninto the trabecular (also known as cancellous or spongy) bone of theskull of the signal or parameter being conveyed through the channel,e.g., for neuromodulation or measurement or energy transfer.

Optionally, the exterior surface of the channel, e.g., the exteriorsurface of the outer layer where an outer layer is provided, may beprovided as threaded, knurled, ridged or otherwise textured so as tohelp fit the channel into the skull and/or to retain it in the skull.Each inner lumen may be provided with the same length, or the innerlumens may have varying lengths.

One or more inner lumens may be fillable, filled or partially filledwith an ion-permeable substance (e.g., a hydrogel), or left open to befilled by the body with one or more of serum, fibrous tissue, or somein-scalp growth.

Each of the inner lumens may be provided with a hexagonal cross-sectionor a cross-section of some other suitable shape (e.g., circular,rectangular). Optionally, the channel may be provided with a lip ortabs, with or without screw holes, to help retain it in position onceimplanted in the skull. If the channel is designed to replace asignificant portion of the skull or part of the skull, then the channelmay be provided with a curvature that approximates the curvature of theskull to be replaced.

In accordance with a still further variation, a transcranial channel isprovided as a thin, cannula-like device (e.g., with a diameter of on theorder of one to several millimeters), such that the overall width of thechannel is much less than the length of the channel. This cannula-likechannel may be formed in whole or in part of an ion-permeable material.The cannula-like channel may be provided with a small bore open at bothends thereof or with an inner lumen surrounded in whole or in part by anouter layer.

In yet another embodiment, a channel for providing a skull/braininterface to facilitate transfer of energy, such as thermal energy, awayfrom the brain is disclosed. The channel is constructed substantiallyfrom a material with high thermal conductivity, and provided with anouter wall, coating, or other covering, constructed from a biocompatiblematerial and, optionally, with a rim or lip to increase the extracranialarea of the device and the area available for heat conduction. Anadditional embodiment may include a channel provided with an interiorcavity that is filled, partially filled, or fillable with a fluid thatmay condense at temperatures cooler than about 32.degree. C. andvaporize at higher temperatures, so that the channel may act as anefficient heat pipe to conduct heat away from the brain.

In still other embodiments, a channel for providing a skull/braininterface to facilitate transfer of energy, such as high-frequencyultrasound energy, towards the brain is disclosed. The channel isconstructed substantially of a material that is mostly transparent toultrasound and has dimensions that are characterized by a substantiallyconstant radius and a substantially constant length to facilitatedelivery of the ultrasound signals to the brain with minimal distortion,thus enabling good focusing of the signals.

The devices, systems and methods further may be used with elements fortemporarily or permanently disabling the conduction of neuromodulationor other interventions to the brain or the transmittal of physiologicalsignals or other information from the brain. Such elements includestoppers and other shields, which may or may not require resection of orincisions into the scalp in order to implement.

Additionally described herein are skull/brain interfaces that includeone or more valves in an interface that can be selectively operated tokeep closed and to fully or partially open each interface for conductionof signals, drugs or other energy from an external source to the brainor transmittal of physiological signals or conduction of energy from thebrain. The valves may be provided with a current or voltage detector, oran active channel device, to monitor and or limit currents or voltagesin the interface at any particular time.

In accordance with yet another embodiment, a transcranial channel may beprovided with a metallic coil or coils or other devices, such as an RFIDchip, to aid in positioning external equipment, such as signal recordinginstrumentation (e.g., EEG machine) or electrical stimulation sources(e.g., pulse generators or DC current generators), relative to thechannel. If the transcranial channel is provided with an external lip,the coil(s) or other device(s) may be provided attached to or embeddedin the lip.

In still other variations, one or more RFID elements may be used toidentify particular patients to external equipment or any other deviceor system with which a skull/brain interface is to be used and for otheridentifying purposes, and to control permissible dosages of stimulationor drugs to the patient (particularly when the patient has some controlover delivery of stimulation or drugs).

In accordance with another embodiment, an extracranial, subcutaneousextension is provided, where the extracranial, subcutaneous extensionextends from the skull/brain interface to a point distant from thecranial breach. For example, the extracranial extension may extend fromthe skull/brain interface to another location on the skull, the neck orthe shoulder.

In accordance with a still further embodiment, a combination of one ormore transcranial channels and one or more transparenchymal channels isdisclosed, where each transparenchymal channel may be formed entirely ofan ion-permeable substance or having an inner lumen that is incommunication with an inner lumen of a transcranial channel. Optionally,an extraparenchymal collector may be used with the combination tofacilitate conduction through the skull/brain interface, and to removethe need for direct mechanical coupling of the transcranial channel(s)to the transparenchymal channel(s).

Also described herein are methods for deploying or implanting one ormore transcranial channels in the skull of a patient by way of acraniotomy, craniectomy (e.g., drilling of a burr hole), and using adilator or series of dilators.

Additionally described herein are systems and methods for identifyingwhere to locate one or more skull/brain interfaces (aperture or channel)including targeting with evoked responses (e.g., TMS-evoked responses)and using overlays and/or low-resolution stereotaxy.

Still further described herein are kits with components for facilitatingskull/brain interfaces including one or more of the following, forexample: an overlay and/or low-resolution stereotaxy assembly; aplurality of channels of various sizes, shapes and lengths; channelswith inner lumens of varying lengths; a scalp electrode pad or scalpelectrode pad or scalp electrode pad assembly; a stimulation source withor without a headpiece or helmet.

Also described herein are systems and methods for gauging skullthickness in a particular patient before or during installation of askull/brain interface, such as an ultrasonic tool or an ultrasonictransducer at the end of a drill.

Further described are methods for deploying or implanting a combinationof one or more transcranial channels and an extracranial extension and acombination of one or more transcranial channels with one or moretransparenchymal channels.

Further described herein are methods for providing an interface throughthe skull to the brain of a patient using one or more transcranialchannels for direct current stimulation, non-pulsatile and near-DCelectrical stimulation, pulsatile and AC stimulation, neuromodulation ortreatment using iontophoresis, and neuromodulation with light.

Further described herein are methods for providing an interface throughthe skull to the brain of a patient using one or more transcranialchannels for neurosensing from the brain, for example, for measurementof an EEG, impedance plethysmography and tomography, and optical imagingand tomography.

Also described herein is a method for providing an interface through theskull to the brain of a patient using one or more transcranial channelsfor conducting heat away from a target area of the brain.

Further described herein is a method for providing an interface throughthe skull to the brain of a patient using one or more transcranialchannels for High Intensity Focused Ultrasound (“HIFU”).

Additionally described herein are aspects of stimulation used withskull/brain interfaces, including limited patient-controlled stimulationin a portable stimulator, remote-controlled stimulators, and currentcontrol and impedance measurement for a stimulation source.

Further described herein are some indications for a skull/braininterface, such as diagnosis of, relief of the symptoms of, or reversalor repair of damage caused by, neurological dsyfunction caused byneurological damage, neurologic disease, neuodegenerative conditionsand/or other conditions. The neurological dysfunction may be related to,for example, epilepsy, movement disorders, traumatic brain injury,cerebral palsy, multiple sclerosis, Alzheimer's disease, dementia,memory disorders, stroke, aphasia, mild cognitive disorders, sleepdisorders, depressive disorders, anxiety disorders, Tourette's syndrome,restless leg syndrome, coma, learning disorders, autism, speechdisorders, auditory or hearing disorders (e.g., tinnitus), craving andaddictive disorders, migraine headaches, and other dysfunctions causedby brain injury or characterized by chronic pain.

Additionally described are some specific systems and methods for using askull/brain interface for particular indications, such as: sleep stagingand selective stimulation; performance-enhancing stimulation (e.g.,vision-enhancing, memory-enhancing, verbal-fluency enhancing, andenhancing creative state); using DC fields for axonal regrowth; using DCstimulation to treat cognitive dysfunction as in Alzheimer's disease;psychiatric disorders; coma; tinnitus, DC stimulation for language andverbal skills; pain, autism, neuroprotection for stroke, and addictionsand cravings.

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects, features, benefits and advantages of the embodiments describedherein will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 is a side, cross-sectional, schematic view of current path in aprior art system and method for applying electrical neurostimulation toa patient's brain.

FIG. 2 is a side, cross-sectional, schematic view of current path in asystem and method according to the invention for applying electricalneurostimulation to a patient's brain.

FIG. 3A is a schematic view of the skull of a patient having skull/braininterfaces according to the invention.

FIG. 3B is a schematic view of the skull of a patient on which a scalpelectrode pad assembly has been situated.

FIG. 4 is a side, cross-sectional, schematic view of a prior art systemand method for acquiring signals for an EEG.

FIG. 5 is a side, cross-sectional, schematic view of a system and methodaccording to the invention for acquiring signals for an EEG.

FIGS. 6-10 each is a perspective view of a variation of a transcranialchannel.

FIG. 11 is a plan view of the transcranial channel of FIG. 10.

FIG. 12 is a perspective view of a variation of a transcranial channelhaving a plurality of inner lumens.

FIG. 13 is a perspective view of a variation of a transcranial channel.

FIG. 14 is a perspective view of another variation of a transcranialchannel.

FIG. 15 is a schematic view of a method of positioning the channel ofFIG. 14.

FIG. 16A is a front view of a variation of a transcranial channel.

FIG. 16B is a schematic view of a plurality of the transcranial channelsshown in FIG. 16A.

FIG. 17A is a schematic view depicting an area of interest in apatient's brain.

FIG. 17B is a schematic view depicting one configuration for deploymentof the transcranial channels of FIGS. 16A and 16B.

FIG. 17C is a schematic view depicting a device positionable over theconfiguration of transcranial channels of FIG. 16B.

FIG. 18A is a side, cross-sectional, schematic view illustrating asystem for removing heat through a skull/brain interface.

FIG. 18B is a perspective view of the transcranial channel depicted inFIG. 18A.

FIG. 19 is a side, cross-sectional, schematic view illustrating a systemfor delivering energy through a skull/brain interface.

FIG. 20 is a perspective view of the transcranial channel depicted inFIG. 17C.

FIG. 21 is a perspective view of a transcranial channel and a shield forclosing off the channel.

FIG. 22A is a cross-sectional of a variation of a transcranial channelin which a two-way valve is provided showing the valve in a closedposition.

FIG. 22B is a cross-sectional and schematic view of the transcranialchannel of FIG. 22A showing the direction of conduction when the valveis an open or partially open position.

FIG. 23A is a perspective view of a transcranial channel having RFIDcapability.

FIG. 23B is a perspective view of a measuring device having RFIDcapability complementary to the transcranial channel of FIG. 23A.

FIG. 24 is a side, cross-sectional, schematic view illustrating a systemfor extending a transcranial channel.

FIG. 25A is a side, cross-sectional, schematic view illustrating asystem for using one or more transcranial channels with atransparenchymal channel.

FIG. 25B is a side, cross-sectional, schematic view illustrating avariation of the system shown in FIG. 25A.

FIG. 26 is a schematic representation of one method of inserting atranscranial channel into the skull of a patient.

FIG. 27 is a schematic representation of a low-resolution stereotaxyassembly positioned on the head of a patient.

FIG. 28A is a schematic representation of a finite-element model (FEM)solution for transcranial direct current stimulation applied to theskull without using a transcranial channel to provide a skull/braininterface.

FIG. 28B is a schematic representation of a FEM solution fortranscranial direct current stimulation applied to the skull using atranscranial channel to provide a skull/brain interface.

DETAILED DESCRIPTION

The inventions are described below with reference to detailedillustrative embodiments. It is apparent that systems according to theinventions can be embodied in a wide variety of forms. Consequently, thespecific structural and functional details disclosed herein arerepresentative and do not limit the scope of the inventions. Further,the embodiments disclosed herein are described in the context ofsystems, methods and devices for providing interfaces between theexterior of the skull and the interior of the skull and/or brain forpurposes of modulating neural activity, detecting, measuring andprocessing parameters characteristic of brain states, and energytransfer from inside the skull to outside the skull or vice versa,because the embodiments disclosed herein have particular utility in thiscontext. However, the embodiments herein can also be used in otherapplications, as will be apparent to those with skill in the art.

FIG. 1 is a cross-sectional, schematic view of a portion of the scalp,skull and brain during transcranial application of current. The currentis applied external to the body from a first pole of a current source(e.g., a pulsatile or DC current source) to a second pole locatedelsewhere (e.g., elsewhere on the patient's head). A layer of conductivegel 14 is disposed between the first pole 10 of the current source andthe scalp 12. Ideally, the current travels from the first pole 10 to thesecond pole (not shown) through a target area 24 in the brain. As apractical matter, however, the current, shown originating from the firstpole 10 with the arrow 16, will be diffused significantly on its way tothe target area 24, because there are paths of lesser resistance throughthe scalp 12, as illustrated by the arrows 18 (in three dimensions, ofcourse, the current would tend to diffuse through the scalp in alldirections, not just in the direction of the arrows 18 shown). (In atypical person, the skull is on the order of 40 times more resistant tocurrent than is the scalp.) What current is directed through the skull20 likewise will be diffuse and only incidentally focused on the targetarea 24, as shown by the arrows 17 in FIG. 1. Moreover, if there shouldbe a naturally-occurring foramen 22 in the skull 20 (a occurrence thatis not all that uncommon), then whatever current is not dispersed in thescalp 12 will tend to flow through the foramen 22, since it is a path oflesser resistance than can be found in the intact skull 20. Thus, evenif the first pole 10 of the current source is accurately positioned overthe area of the brain 24 to be targeted for neuromodulation, currentwill tend to flow elsewhere than towards the target area if a foramen islocated outside the area of the skull that corresponds to the targetarea of the brain.

A method of providing a brain/skull interface now will be described withreference to FIG. 2. A skull/brain interface is created by accessing aselected area on the exterior of the skull, for example, by making anincision through the skin 30 and the scalp tissue 32 to create a flapand folding the flap back. An aperture 34 is formed in the skull using adrill or other suitable instrument over a target area 24 of the brain.

In FIG. 2, the aperture 34 extends through all layers of the skull,i.e., through the outer layer of cancellous bone 36, the spongiform bone38, and the inner layer of cancellous bone 40, and breaches the innerlayer of cancellous bone so that the aperture is exposed to theextradural space 42. In a variation of the method, the aperture 34 maybe formed so that it extends only part way through the skull 20. Forexample, the aperture 34 may be formed so that it extends through allthree layers of the skull but is just short of breaching the inner layerof cancellous bone 40 so as to not breach the extradural space 42.

In variations where the aperture 34 does not extend all the way throughto the extradural space, conduction through the aperture 34 may besomewhat less efficient than in the case where the aperture 34 extendsthrough to the extradural space. However, these variations may bepreferred when it is desired to avoid penetrating the skull entirely,for example, to lower the risk of infection. In one embodiment, theaperture 34 is formed so that it extends through about 90% of thethickness of the skull 20.

Although the aperture 34 shown in FIG. 2 is generally cylindrical, theaperture can be formed with other shapes, provided that there is asubstantially direct path through the aperture 34, as indicated by thearrow 44, through which conduction can occur. (Although not shown inFIG. 2, it will be understood that, if the skull/brain interface isbeing used to conduct away from the target area 24 to the exterior ofthe skull, then the arrow 44 would be pointing in the oppositedirection.)

After the aperture 34 is formed, the surgeon may flush or purge theaperture 34 with a saline solution to cleanse the area and otherwiseprepare it for immediate use.

The flap in the scalp is then replaced (or the scalp is otherwiserepositioned over the aperture 34) and the site of the incision issutured or otherwise closed.

If the skull/brain interface is to be used for conducting a form ofneuromodulation to the brain target area 24, then the neuromodulationsource is situated in the vicinity of the proximal end of the aperture34, i.e., the end of the aperture at the outer layer 36 of the skull.This may be accomplished immediately after the aperture 34 is formed andthe scalp flap is replaced, or some period of time later. It will beappreciated, however, that the body's natural response to the formationof the aperture 34 may be healing or tissue proliferation, which maycause partial or complete re-closure of the aperture 34 over time. Whilethis response may well be desirable as, for example, when theneuromodulation is only intended to be delivered in a short-term courseof therapy or for a rehabilitation period, the time lag betweenformation of the aperture 34 and association with the neuromodulationsource should be calculated with the possibility of re-closure in mind.

The neuromodulation source shown in FIG. 2 is a current source (fordelivering pulsatile, DC, or nonpulsatile/near-DC stimulation), althoughit will be appreciated that other neuromodulation sources can besubstituted for the current source, such as a source for opticalneuromodulation or a source for iontophoretic delivery of substances.

When the neuromodulation source is a current source, a layer ofconductive gel 14 optionally can be provided between the first pole 10of the current source and the skin of the scalp in the vicinity of theproximal end of the aperture 34, i.e., the end of the aperture at theouter layer 36 of the skull. Alternatively, other means for improvingconduction from the neuromodulation source to the aperture 34 may beprovided. In one variation as a sponge soaked in saline may be providedfor conduction.

In another variation, and referring now to FIGS. 3A and 3B, one or morescalp electrode pads 46 may be provided that can be placed between theexternal current source and the scalp, over or in the vicinity of theskull/brain interface(s) (e.g., aperture(s) or other fenestration(s). Aplurality of apertures 34 are shown in FIG. 3A. Each scalp electrode pad46 is formed at least in part from a conductive material or substance,so that when put in place between the current source, on the one hand,and the scalp and the apertures, on the other hand, current willpreferentially be delivered to the apertures 34 associated with theconductive material or substance.

With further reference to FIG. 3B, one or more scalp electrode pads 45may be provided in a scalp electrode assembly 46. In one variation, ascalp electrode pad 45 may be connected to a stimulation source (notshown in FIG. 3B) via at least one lead 47. In a variation, anon-conductive strip of material may extend between a scalp electrodepad 45 and an electrode being used as a reference electrode forstimulation (or measurement) (not shown in FIG. 3B), in order to controlthe relative position of the electrodes. The scalp electrode padassembly 46 may be provided with an optional feature that allows it tobe oriented on the head with respect to some anatomical marker orlandmark, such as a traditional landmark used in positioning electrodesfor EEG, for example, a nasion. The orienting feature 48 shown in FIG.3B is intended to be positioned relative to a patient's ear. The scalpelectrode assembly 46 may further be provided with an optional featurefor aiding in securing the assembly on the patient. The securing feature49 shown in FIG. 3B, is a strap.

Although the scalp electrode pads and assembly are described herein withreference to facilitating conduction from an external source ofneuromodulation into the brain, it will be apparent to one skilled inthe art that the scalp electrode pads and assembly may also be used tofacilitate detecting physiological information from the brain asdescribed herein.

When the stimulation source is activated, and owing to the presence ofthe aperture 34, current will flow in the direction of the arrow 16 andthe arrow 44, in a substantially direct path to the target area 24 ofthe brain at which neuromodulation is desired to occur. Some currentwill be diffused through the scalp 12, as indicated in FIG. 2 by thearrows 18, but the degree of diffusion will be much less than in thecase where no aperture 34 is formed. Some current also will be diffusedthrough the spongiform bone 38 through which the aperture 34 extends.Again, however, the amount of diffusion will be less than in the casewhere neuromodulation is attempted through an intact skull. The methodof providing a skull/brain interface also can be applied to conveyinformation externally to the skull from or about one or more brainstates, for example, for an EEG or for other neurosensing modalities,including but not limited to impedance plethysmography and tomographyand optical imaging and tomography. In one variation, the location forthe aperture 34 is selected so that it will be over a target area 24 ofthe brain from which it is desired to sense electrical signalscorresponding to neural activity for an EEG. The aperture 34 is formedand prepared for use in the manner described above with respect to FIG.2.

FIG. 4 illustrates one conventional method for acquiring signals for anEEG. Scalp electrodes 50 a-50 d are shown placed on the scalp over thetarget area 24 of the brain from which electrical activity is desired tobe measured. The area of the brain that will contribute signals to themeasurements obtained from scalp electrode 50 a is illustrated by thedashed line 52, and the area of the brain that will contribute signalsto measurements obtained from scalp electrode 52 b is illustrated by thedotted line 54. Areas 52 and 54 are relatively large and overlap eachother significantly because the presence of the skull impedes thespatial resolution of the electrodes 50 a-50 d and contributes toblurring of the electrical potentials that are sensed by the electrodes.

Referring now to FIG. 5, a method of providing a skull/brain interfacefor acquiring signals for an EEG is illustrated. Four apertures 34 areshown formed in the skull 20 over the target area 24. After the scalp isreplaced over the apertures, scalp electrodes 50 a-50 b are placed overthe proximal ends of each aperture 34. As illustrated by the dashedlines 52 and 54, the two areas of the brain that will contribute to thesignals measured by the electrode 50 a and 50 b are much smaller than inthe case of the conventional EEG measurement. In addition, the areas 52and 54 have little overlap with each other. Thus, the spatial resolutionof the signals sensed is improved upon, and the resultant measurementwill be characterized by less blurring than in when a conventionalmethod for obtaining an EEG is used.

While four apertures 34 are shown in FIG. 5, any number of apertures maybe used in connection with the method.

Although the method of providing a skull/brain interface for sensing aparameter characteristic of a brain state has been described inconnection with sensing electrical activity for an EEG, it will beappreciated that other neurosensing modalities can be achieved with themethod.

For example, electrical impedance measurements at different frequenciesmay be obtained through the apertures 34 for estimating the volume of ananatomical space, as in impedance plethysmography. The impedancemeasurements may be used to map plethysmographic changes in the brain,as in Electrical Impedance Tomography (EIT). By providing a well-definedpath through the otherwise relatively nonconductive skull, improvementsin spatial resolution and degree of blurring may be realized with thismethod over conventional methods for performing similar techniques.

It will be appreciated that regardless of the purpose of the skull/braininterface and the relative time the aperture is intended to remainpatent (e.g., for acute or chronic procedures), the apertures could beclosed off with plugs designed to fit in the channels or into a socketassociated with the aperture to, for example, block ion movement throughthe aperture and/or to discourage infection in the brain cavity. Theplugs could be used to disable the aperture for its intended usetemporarily or to close off the channel permanently when it is no longerneeded.

Transcranial Channels

A device and method of providing a skull/brain interface will now bedescribed with reference to FIGS. 6-17.

FIG. 6 illustrates a variation of a transcranial channel 100 that isintended for insertion in an aperture formed in the skull of a patientto provide a skull/brain interface, e.g., for delivering a form ofneuromodulation to the brain, sensing a parameter or parameters from thebrain, or transferring heat from the brain exteriorly of the skull. Thetranscranial channel 100 is generally cylindrical, but it will beappreciated that the channel may be provided with any shape providedthat the shape selected allows for a substantially direct path from theexterior of the skull through the channel.

The channel 100 has an outer wall 102 that defines an interior cavity104. The outer wall provides mechanical stability to the channel and isformed from a biocompatible material. The biocompatible material mayinclude but is not limited to a metal such as titanium or stainlesssteel, or a biocompatible polymer (e.g., polyurethane,polytetrafluoroethylene, polyetheretherketone, polyester, polyamide(e.g., nylon)).

The biocompatible material of the outer wall 102 may be formed from amaterial that is not generally permeable to ions to discourageconduction in a path other than the desired path. Alternatively, theouter wall 102 may be provided with a coating on all or a portion of theouter wall 102 that includes a generally non-ion-permeable substance forthe same purpose of discouraging unwanted conduction. (Non-ion-permeablemetallic, biocompatible substances (e.g., titanium or stainless steel)are usually suitable for use in the outer wall when the channel isintended for use in connection with the application of DC stimulationbecause the voltage at the metal-to-tissue interface developed bytypical stimulation amplitudes is usually not sufficient for conductionof DC current into or out of the metallic substance itself.)

The channel has a proximal end 106 that is intended to be oriented atthe proximal end of the aperture 34 into which the channel is inserted,i.e., the end of the aperture at the outer layer 36 of the skull. Thechannel has a distal end 108 that is intended to be oriented towards thebrain. In FIG. 6, the proximal and distal ends 106, 108 are left open tothe air, or (when implanted) to the sub-scalp and extradural space,respectively, which eventually may result in the channel being filled orpartially filled with ion-permeable body serum or tissue.

In other variations, a channel 100 may be provided with an end cap orcover for one or both of the proximal and distal ends 106, 108, forexample, in the form of a membrane manufactured from a suitablebiocompatible material. The end cap(s) or cover(s) may be providedaffixable or affixed to the channel and nonremovable, or affixable orfixable to the channel and removable. Suitable materials for an end capor cover may include but are not limited to porous silicone, porouspolyurethanes, or a mesh or grid of any non-porous biocompatiblepolymers.

An end cap or cover may be desirable to help retain a substance that isused to fill or partially fill the interior cavity, such as a hydrogelor saline solution. A cover in the form of a membrane on one or both ofthe proximal and distal ends 106 and 108 of the channel 100 may bedeemed especially desirable in some circumstances. For example, afterthe channel has been implanted, a membrane may discourage migration ofany bacteria or pathogens that might be present in the subcutaneousspace into the intracranial space.

In the case where a transcranial channel is intended to be used forneuromodulation by iontophoresis, a semipermeable membrane may beprovided for a cover to prevent iontophoresis of large or otherwiseundesirable molecules into the intracranial space.

In still other variations, a channel 100 may be provided without an endcap or cover but with the cavity 104 filled or partially filled with asubstance that is understood or believed to facilitate conduction forthe particular application for which the channel is to be used. Forexample, in an application where the channel is intended to be used tofacilitate DC stimulation of a target area of the brain, the cavity 104may be filled with an ion-permeable substance such as porous silicone,porous polyurethanes, saline solutions, hydrogels, or porous massesconstructed by sintering together particles of a nonporous polymer suchas polyurethanes, polytetrafluoroethylene, polyetheretherketones,polyesters, or polyamides (e.g., nylon). In another example, the cavity104 may be may be filled, partially filled or fillable with a substancesubstantially in the form of an open-pore sponge infiltrated with anantiproliferative agent, for example bone morphogenic proteins, ciliaryneurotrophic factor, ribavirin, sirolimus, mycophenolate, mofetil,azathioprine, paclitaxel, cyclophosphamide, or atomic silver, where thepresence of the antiproliferative agent may prevent cell proliferationand tissue growth after the channel has been implanted in the skull.

The cavity 104 may be filled or partially filled with the ion-permeablesubstance at the time it is placed in the skull or, if end caps areprovided, at some time before deployment (e.g., at the time ofmanufacture or as a part of the preparation for the surgery).

The channel 100 may be provided with a length 1 that is designed totraverse the entire thickness of the skull. In other variations, thelength 1 of the channel may be designed to traverse only part of the waythrough the skull. For example, the channel might be provided with avery short length l relative to the thickness of the skull, such that itprovides a sort of a lid for the aperture upon implantation (see, e.g.,FIGS. 14 and 15). In another example, the channel might be provided witha length l that approximates about 90% of the thickness of the skull.These latter variations may be preferable to use when it is desirable toavoid breaching the inner layer 40 of the skull 20 with the channel 100.The conduction of signals through the channel 100 will be less efficientthan in the case where the channel traverses the entire thickness of theskull, but will still be more efficient than if no channel at all wereused to facilitate conduction or otherwise to provide a skull/braininterface. In these variations, it is expected that it would bedesirable to provide channels with a thickness, l, that is designed tobe about ten percent less thick than the skull thickness, in order toavoid penetrating the skull entirely but nevertheless affording goodconduction through the channel.

In FIG. 6, the channel 100 has an overall width, w, corresponding to thediameter of the cylinder, that is approximately the same as the lengthl, although it will be appreciated that the ratio between the overallwidth w and the length l may be varied to best serve the application(s)to which the channel is intended to be put.

Another variation of a transcranial channel 100 is shown in FIG. 7. Thechannel 100 is provided in the form of a plug 140 formed from a materialwell suited for the intended application of the channel. The materialmay be an ion-permeable substance when an intended application is to usethe channel to facilitate DC stimulation of the brain. In FIG. 7, thechannel is shown having a generally cylindrical shape that ischaracterized by a taper so that the plug narrows from the proximal end106 to the distal end 108. The taper may help prevent the channel 100from being pushed into the aperture formed in the skull to a greaterdegree than intended. Other variations of the plug 140 may be providedhaving different shapes as was the case of the channel 100 described inconnection with FIG. 6, above. Other variations of the plug 140 may beprovided with different ratios of overall width to length, and withdifferent angles of taper or no taper at all.

Still another variation of a channel 100 is shown in FIG. 8. Thisvariation is similar to the tapered variation of FIG. 7 however, thisvariation an outer wall 102 and an interior cavity 104 into which,optionally, a substance such as an ion-permeable substance (other thanair) may be introduced.

In FIG. 9A, a variation of a channel 100 is shown in which an interiorcavity 104 is defined by an outer wall 102 and the exterior surface 160of the outer wall 102 (i.e., the surface opposite the surface adjacentthe interior cavity) is provided with ridges 162. The ridges 162 mayassist in securing the channel 100 in the skull. In other variations,the exterior surface 160 may be knurled, threaded or otherwise textured.Any of these exterior surfaces 160 are likely to increase the forcesbetween the exterior surface and the skull to help keep the channel 100in the desired position.

The channel 100 optionally may be provided with a rim or lip 164 thatextends outwardly from the proximal end 106 of the channel. The rim orlip 164 may be formed from the outer wall 102 or the lip 164 may beprovided as a separate component of the channel 100, as is shown in FIG.9A. The lip 164 will help keep the channel in the desired position inthe skull and will help to prevent the channel from being pushed furtherinto the skull than intended.

In still another variation of the channel 100, as illustrated in FIG.9B, the channel is provided with a lip 164 extending out from theproximal end 106 of the channel having screw holes 168. After thechannel 100 is placed in the desired position in the skull, screws canbe screwed into the skull through one or more screw holes 168 to helpmaintain that position. The number of screw holes 168 that are providedin a given channel 100 may vary with the size of the channel, forexample, a channel having a relatively large overall width may beprovided with more screw holes than a channel with a relatively smalloverall width.

Referring now to FIGS. 10 and 11, a variation of a channel 100 is shownhaving an overall width, w, that is much greater than its length, l, anda plurality of inner lumens 180 defined in the interior cavity 104. Thelength l of the channel 100 may be selected to approximate the thicknessof the skull, so that when the channel is in position in the skull, thechannel will traverse the entire thickness of the skull. Alternatively,the channel may be designed to traverse almost, but not all, of thethickness of the skull to avoid breaching the inner layer 40 of theskull. When a channel of this greater overall width is indicated,providing the plurality of inner lumens will enhance the mechanicalstability of the channel. The plurality of inner lumens will alsoprovide a mechanical barrier in what would otherwise be a relativelylarge open space between the outer and inner layers of the skull, andthus may prevent inadvertent breaches of that space with undesiredobjects (e.g., a finger or instrument during implant or during anapplication such as delivery of neuromodulation).

The length, l_(sl), of the each of the inner lumens 180 may be the sameas or approximate the length, l, of the channel 100. In FIG. 12, eachlumen lengths, l_(sl), is approximately the same as every other lumenlength, l_(sl), and the lumen lengths are less than the length, l, ofthe channel. Optionally, one or more of the inner lumens 180 may havedifferent lengths, l_(sl), and one or more of the lengths, l_(sl), maybe less than the length, l, of the channel 100.

Each of the inner lumens 180 is characterized by a cross-section that isgenerally hexagonally shaped, but many other shapes useful forparticular applications of the channel 100 will be apparent to thoseskilled in the art. The inner lumens 180 may be formed as sub-lumens inthe interior cavity from a single starting piece, e.g., with a mold ormolding process. In this case, the portion 182 of the interior cavity104 between the walls 184 of the plurality of inner lumens 180 and theouter wall 102 may be filled in, i.e., formed from a solid or semi-solidpiece of material, such as the same material that is used for the outerwall 102, and may be an extension of the outer wall 102. In anothervariation (not shown in FIG. 10 or 11), each inner lumen 180 may beindividually formed and inserted into the interior cavity 104. In thiscase, the portion 182 of the interior cavity 104 between the walls 184of the plurality of inner lumens 180 and the outer wall 102 may be leftas a part of the interior cavity 104, i.e., left open to the air (to belater filled or partially filled with serum, among other things, whenthe channel 100 is positioned in the skull).

The outer wall 102 may be formed from a substance that is non-ionpermeable or that contains non-ion permeable material, e.g., to minimizethe loss of current from the channel to the trabecular bone (middlelayer) of the skull when the channel is used to conduct current.Alternatively, one or more surfaces of the outer wall 102 may beprovided with a coating containing a non-ion permeable material for thesame purpose.

The channel 100 with the plurality of inner lumens 180 of FIG. 10 isprovided with an optional lip 164 to assist in maintaining the channelat the desired position in the skull and to prevent the channel frominadvertently being pushed further in towards the brain than desired.One or more screw holes (not shown) may be provided in the lip so thatthe channel may be secured with one or more screws to the skull once thechannel is positioned at the desired location.

FIG. 13 illustrates another variation of a transcranial channel 100having a plurality of inner lumens 180. In this variation, the channel100 is formed from a single piece 188 of starting material, e.g., by aninjection molding process. The inner lumen lengths, l_(sl), may bedifferent than the overall length, l, of the channel 100, e.g., l_(sl),may be greater or less than l for a given inner lumen 180.

The channel 100 of FIG. 13 does not have a lip that is designed toextend over or rest on the outer surface of the skull when the channelis positioned transcranially. However, the channel 100 of FIG. 13 isprovided with tabs 190 that are formed as a part of the piece ofstarting material 188 and which extend outwardly from the top surface ofthe channel. Each tab 190 is provided with a screw hole 168 throughwhich a screw may be inserted at the time the channel is deployed in theskull to help anchor the channel at the desired location. Alternatively,the tabs 190 may be formed of a material different from that of thestarting material 188 and more suitable for mechanically anchoring thechannel 100 in the skull; for example, titanium tabs 190 used to anchora polyetheretherketone starting material 188. In another variation, thetabs 190 may be replaced or augmented by a substantially continuous lip164 (not shown in FIG. 13).

The channel 100 shown in FIG. 13 has an overall width, w, that is muchgreater than its length, l, and the length, l, is chosen so as toapproximate all or most of the thickness of the skull. Therefore, thechannel 100 is intended to extend over a fairly significant portion ofthe patient's skull. Accordingly, the variation of the channel 100 inFIG. 13 is provided with a curvature, c, that is intended to approximatethe natural curvature of the patient's skull where the channel is to belocated when in use.

Referring now to FIGS. 14 and 15, still another variation of a channel100 is illustrated that has an overall width, w, that is much greaterthan its length, l. Moreover, the length, l, of the channel 100 is alsomuch less than the thickness of the skull Thus, this variation ischaracterized by a short interior cavity 104. This channel is designedto fit into or over the proximal end of the aperture formed to accept it(i.e., the end of the aperture at the outer surface of the skull) in themanner of a lid, with the channel length, l, intended to extend slightlyabove the surface of the skull rather than to traverse any significantportion of the thickness of the skull. The channel 100 shown in FIG. 14is shown with an optional rim or lip 164 and screw holes 168 that may beused to help secure the channel 100 to the outer surface of the skull.The channel 100 shown in FIG. 14 is further optionally provided with amesh-like structure 191 formed in the interior cavity 104. Thismesh-like structure 191 may provide mechanical stability to the channeland may prevent inadvertent breaches of the skull aperture space withundesired objects (e.g., a finger or instrument during implant or duringan application such as delivery of neuromodulation).

FIG. 15 schematically illustrates a method by which the channel 100 ofFIG. 14 may be deployed. First, an aperture 192 is formed over a targetarea 24 of the brain (e.g., a target for neuromodulation and/or forsensing parameter from the brain). The size of the aperture willapproximate the overall width, w, of the channel 100 that is intended tosit in or over the aperture. The channel 100 is then inserted into theaperture and, if screw holes 168 are provided in a lip 164, the channel100 may be secured to the outer surface of the skull 36 with screws (notshown).

Variations of the channel 100 illustrated in the Figures show channelswith a gross shape that is generally circular or rectangular in planview. However, it will be appreciated by those skilled in the art thatmultiple other shapes may be provided to best suit the intendedapplication of the channel. Fundamentally, considerations of mechanicalstability for the deployed channel may inform the overall size and shapeof the channel, as well as the number and configuration of any innerlumens that are provided. In addition, the overall size, shape andnumber of inner lumens provided, if any, may be driven by the intendedapplication(s) for the channel and the target area(s) of the brainassociated with those applications. For example, a single channel may bedesigned to provide a skull/brain interface for multiple applicationsusing multiple target areas of the brain. In this case, the overallshape of the channel in plan view may be tailored for the applicationand/or for the target area, e.g., to match the overall dimensions ofeach target area. Similarly, if a channel is provided with a pluralityof inner lumens, the size and shape of the cross-sections of these innerlumens may vary within a given channel to suit multiple applications forthe channel (e.g., delivery of neuromodulation and measurement of EEG)and/or to accommodate the different dimensions of different target areasof the brain.

FIGS. 16A-16B and FIGS. 17A-17C illustrate still other variations of atranscranial channel 100. FIGS. 16A and 16B depict a channel 100 havingan overall width, w, that is much less than its length, l. Since thechannel length, l, is designed to approximate the entire thickness orsubstantially the entire thickness of the skull of the patient in whomthe channel is to be implanted transcranially, the channel of FIGS. 16Aand 16B is generally small or fine and cannula-like. In one variation,the cross sectional diameter of the generally cylindrical cannula-likechannel 100 is on the order of 1 to 2 mm, as compared with a typicalskull thickness on the order of 5 mm. The channel may be formed from abiocompatible polymer to resemble a thin-walled straw.

The channel 100 may be provided in the form of a solid or semi-solidplug of material as described with respect to FIG. 7, optionallycharacterized by a taper from the proximal to the distal end.Alternatively, and as shown in FIGS. 16A and 16B, the channel 100 may beprovided with an outer wall 102 that defines an interior cavity or smallbore 194. The small bore 194 may extend all the way through the channel100 so that it is contiguous with the outer wall 102 and open to the air(or, when implanted, to the intracranial space) at the distal end 108 ofthe channel. Optionally, the small bore 194 may be provided with one ormore end caps (not shown), for example, in the form of a thin membraneof material, in order to retain a substance that may be provided in thesmall bore 194, e.g., an ion-permeable substance or a pharmaceuticalsubstance.

The channel 100 shown in FIGS. 16A and 16B has a generally circularcross section, but it will be appreciated by those skilled in the artthat the channel may be provided with cross sections of other shapes,such as square, oval, rectangular, hexagonal, etc. The cross-sectionalshape may be a design consideration with respect to one or more of thefollowing: the mechanical stability of the channel during or afterimplantation, the ease with which the channel may be manipulated duringimplantation, and the efficiency with which the channel can conductthrough the skull to the target areas of the brain.

One or a plurality of these small bore channels 100 may be used with agiven patient, depending on the desired application for the skull/braininterface provided by the channel(s). If a plurality of the small borechannels are used, the channels may be grouped together, asschematically represented in FIG. 16B (with the shaded area 196representing the skull). Alternatively, relatively many small-borechannels 100 may be used to cover different target areas of the brain.

For example, FIGS. 17A-17C illustrate one possible deployment ofsmall-bore channels 100 to cover a fairly large area of the underlyingbrain, depicted by the shaded area 200 in FIG. 17A. This area mayrepresent multiple target areas 24 for one or more applications of theinterface (e.g., delivery of neuromodulation to the brain, heat transferfrom the brain exteriorly of the skull, measurement of an EEG, etc.).FIG. 17B shows a plurality of small-bore channels 100 implantedtranscranially over the shaded area 200. (One method for implanting thesmall-bore channels is described hereinbelow.)

FIG. 17C shows a device 202 that is positionable over the plurality ofimplanted small-bore channels 100, which device may be capable offacilitating one or more of delivering a source of neuromodulation to atarget area of the brain, removing heat from a target area of the brain,or sensing a parameter through the interface that is believed orunderstood to be characteristic of a brain state.

In still other variations, transcranial channels 100 may be designed forthe purpose of conducting heat away from a target area 24 of the brainvia thermal conduction (i.e., as opposed to, for example, conductingelectric current via ion movement). One application of one or more ofthese channels may be to draw heat away from an epileptic focus in thebrain with the goal of stopping or avoiding seizures. Channels designedfor this purpose may be used alone or in conjunction with one or moredevices applied external to the scalp to help draw the heat away fromthe brain and/or to act as a reservoir for the heat as it is removed.

FIGS. 18A and 18B illustrate a transcranial channel 100 designed for thepurpose of providing a skull/brain interface through which heat can bewithdrawn from the interior of the skull. The channel 100 is formedsubstantially from a material characterized by a high thermalconductivity 220, for example, in the range of 300 to 500 Watts permeter-Kelvin, such as copper or silver. The channel may be provided withone or more rods formed from the high thermal conductivity material 220.

For biocompatibility, it may be necessary to dispose a layer or coating222 of a biocompatible material over or substantially over the materialwith high thermal conductivity. Such a layer or coating may beconstructed of a biocompatible material with low thermal conductivity,for example titanium, since the channel 100 is formed substantially froma material characterized by a high thermal conductivity 220.

Optionally, the channel 100 may be provided with a rim or lip 164 toincrease mechanical stability in the skull and to increase theextracranial area of the device and, thus, the area available for heatconduction to the scalp. It will be appreciated by those skilled in theart that a channel 100 constructed as described here to facilitatetransfer of heat may also facilitate conduction of electrical current inthe form of ion movement, if one or several ion-permeable lumens isprovided within the material characterized by a high thermalconductivity 220.

Although a single channel 100 is shown in FIG. 18A, it will beappreciated by those with skill in the art that a plurality of channelsmay be useful for particular applications intended for heat transfer.Similarly, certain applications may benefit from channels characterizedby a relatively large overall diameter, as shown in FIG. 11 and FIG. 13,with or without a plurality of inner lumens, or from the cannula-likechannels shown in FIGS. 16A-16B and FIG. 17B.

Other variations of a transcranial channel for use in drawing heat awayfrom the brain may be based on the principle of operation of a heat pipecommonly used for cooling electronic devices. Heat pipes may beconfigured in a number of ways, but typically are hollow metal tubescontaining a working fluid. In one such variation of a transcranialchannel, a heat pipe could be provided in the form of a hollow metaltube capped at the proximal and distal ends thereof, designed to extendthrough the thickness of the skull with the distal end of the tubeintended to be oriented near a target area of the brain from which heatis to be removed, and the proximal end of the tube intended to bepositioned towards the outer skull or scalp. A wicking substance orstructure such as a nonsoluble fibrous material, sintered metal powder,or series of grooves oriented in the distal-proximal axis may besituated within this chamber or on its interior walls to furtherfacilitate heat pipe action. A working fluid could be provided withinthe hollow tube such as water, the water being maintained at a pressuresuitable to maintain the majority of the water in the pipe as watervapor until a receptacle for the heat to be transferred from the brainis brought into proximity of the proximal end of the channel. When thereceptacle is present, the water vapor in the heat pipe near the coolingdevice condenses, transferring heat to the cooling device, and theadditional water in the heat pipe near the brain evaporates, removingheat from the brain. As long as there exists a temperature differentialbetween the brain and the receptacle or external heat reservoir, thetranscranial channel provided with the heat pipe can operatecontinuously to cool the brain.

In still other variations, transcranial channels may be designed tofacilitate the delivery of energy to the brain, for example, in a highintensity focused ultrasound (“HIFU”) application wherein ultrasound isused to ablate brain tissue or create lesions in the brain. Referringnow to FIGS. 19 and 20, a transcranial channel 100 is formed from amaterial that is understood to be largely transparent to ultrasound(e.g., an acrylic material). The dimensions of the channel 100 arecharacterized by a substantially constant radius, r_(c), and asubstantially constant length, l_(c), to facilitate passing theultrasound signals 228 from an ultrasound source 230 through theskull/brain interface with minimal distortion, thus allowing forrelatively precise and accurate focusing of the ultrasound onto thetarget area(s) 24 for one or more procedures (e.g., to surgical ablationof brain tissue or one or more ultrasound procedures to create preciselesions in the brain without requiring additional, more invasivesurgery). The channel 100 may be provided with a lip 164 to minimize therisk of inserting the channel further into the skull than intendedduring or after the channel is implanted.

Any transcranial channel or plurality of transcranial channels describedherein can be associated with an element or elements for closing off thechannel(s), temporarily or permanently. An element may be in the form ofa stopper with dimensions designed to fit in the part or parts of thechannel that otherwise would be open to conduction.

If the channel is filled or partially filled with a substance other thanair, the element could be a shield that covers the conducting portionsof the channel to discourage conduction. A shield and a skull/braininterface may each be provided with features that are designed to matethe shield with the skull/brain interface when the shield is deployed,such as a fitting in the shield that is designed to be inserted into asocket provided on a channel or vice versa.

The elements for closing off the channels may be designed to betemporary (for example, so that they can be removed while DC stimulationis being delivered and then replaced) or permanent (for example, so thatthey can be used when the channels are to be permanently disabled suchas when a treatment plan has been completed).

The element or elements for closing off a channel or a plurality ofchannels may be affixed via minor surgery which may or may not involveresecting the scalp in the area of the channel in order to install theelement(s), and then replacing the scalp over the area. FIG. 21illustrates a shield 232 that may be used to close off a transcranialchannel 100 having a plurality of inner lumens 180. When the shield 232is fitted over the proximal end 106 of the channel, conduction throughthe channel (for example, ion conduction) may be prevented eithertemporarily or permanently if the shield is formed from a material thatis generally impermeable to ions (e.g., metal). While devices andmethods for temporarily or permanently closing off channels have beendescribed above, it will be apparent to one skilled in the art that thesame or similar devices and methods may be used to temporarily orpermanently close off apertures or preexisting or naturally-occurringfenestrations used or intended for use in facilitating focusedneuromodulation or sensing of physiological signals from the brain orany methods disclosed herein (e.g., iontophoresis).

In still other variations, any transcranial channel or plurality oftranscranial channels described herein can be provided with a valve orvalves to selectively allow the channel(s) to conduct. For example, andreferring now to FIGS. 22A and 22B, a transcranial channel 100 having anouter wall 102 defining an interior cavity 104. The channel 100 is shownprovided with a plurality of inner lumens 180 each having a lengthl_(sl). A bicuspid valve 234 is shown with a first flap 235 a and asecond flap 235 b. In FIG. 22A, the valve 234 is in a closed positionand the first and second flaps 235 a and 235 b form a surface whichdiscourages conduction through the channel in the direction from theproximal end 106 to the distal end 108. In FIG. 22B, the valve 234 isshown in an open or partially open position, with the first and secondflaps 235 a and 235 b each displaced from their closed positions toallow conduction through the channel in the direction of arrow 236(i.e., in the direction from the proximal end 106 to the distal end108). The plurality of lumens 180 are included in a proximal endstructure 103. The proximal end structure 103 includes at least oneextension 105 that extends into the interior cavity 104 of the channel100 toward the distal end 108 of the channel. The proximal end structure103 is coupled to the outer wall 102 in a manner that provides fordisplacement of the proximal end structure relative to the outer wall,as evident from FIGS. 22A and 22B.

The valve 234 can be configured to transition from a closed position toan open or partially-open position by mechanical means, such as apressure sensitive mechanism that cause the valve to open or close whenpressure is applied to the valve, for example at a proximal surfacethereof. Alternatively, the valve 234 can be configured to open andclose by magnetic means (e.g., when a magnet is placed near the valve,the valve closes or opens). The valve may be configured to operate withother means, such as electrically, as will be apparent to those withskill in the art.

Similarly, and although a bicuspid valve is illustrated in FIGS. 22A and22B, valvular action may be implemented in a channel 100 with any one ofa number of different types of valves, singularly or plurally.

A combination of a channel or channels 100 and a valve or valves 234 maybe configured so that the valve(s) 234 open or partially openselectively, for example, only when a stimulus is present for a certainperiod of time. The combination may also be configured together with afeature or features in the channel, the valve and/or in any externalequipment with which the channel is intended to be used, so that thevalve can only open when certain external equipment is recognized orpositioned closely enough to the channel to be safe or effective.Alternatively or additionally, the combination could be configured withfeatures in one or all of the elements so that the valve will close if,for example, external equipment is removed or taken out of apredetermined range, or certain limits for stimulation or exposure timesare exceeded.

In some variations, a combination including a valved transcranialchannel may be provided with a current or voltage detector. A currentdetector may direct the soft flaps 235 a and 235 b to close or remainclosed when the amount of current being provided from a source (e.g., asource of neuromodulation coming from external equipment or from asource associated with such equipment) surpasses a threshold to, forexample, prevent excessive stimulation from passing through the channel100. In other variations, a combination including a valved transcranialchannel may be provided with an active channel device (i.e., a channeldevice equipped with active electronics and having or associated with apower source) that is capable of sensing voltages, for example, at theinner and outer tables of the skull or between at least two points alongthe length of the channel 100. These voltages may be used to compute theamount of current in the channel 100 at any particular or predeterminedtime.

The valve feature also may be used beneficially in conjunction with theRFID capability described below.

In another variation, any of the transcranial channels 100 describedwith reference to FIGS. 6-16 may be provided with an RFID (RadioFrequency Identification) capability, to provide a reference that willaid in the positioning of other equipment that is to be used with thetranscranial channel, such as an external stimulation or recordingdevice. For example, and with reference to FIGS. 23A and 23B, a channel100 is provided with first and second passive RFID controllers 240 and242. The passive RFID controllers 240 and 242 may be embedded in thepiece 188 from which the channel is formed or may otherwise be affixedor attached to the channel 100. First and second receiver antennas 244and 246 are provided disposed about or near the first and second passiveRFID controllers 240 and 242, respectively.

RFID features can also be used to good effect with transcranial channelsto prevent a particular channel from being used with other thanauthorized external equipment and devices, such as stimulation devicesand equipment to measure and/or store signals sensed through thechannel. For example, one RFID element in a channel can be associatedwith another RFID element in the external equipment such that only thatequipment can be used for that channel in that patient.

The RFID element(s) can be used to identify particular patients to theexternal equipment or to any other device or system, such as a device orsystem designed to identify which patients have skull/brain interfaces,or which skull/brain interfaces are in which patients, or whichskull/brain interfaces are permissible for use with certainneuromodulation sources or sensing equipment, etc. Similarly, the RFIDelements can be used to control permissible dosages of stimulation ordrugs, especially when delivery of the stimulation or drugs is wholly orpartially under the control of the patient (e.g., the RFID elementsmight be configured to prevent the patient from delivering more than aprescribed amount of stimulation to himself or herself per day).

Referring now to FIG. 23B, the RFID capability in the channel 100 ofFIG. 23A may be complimented with a device 252 associated with theapplication for which the skull/brain interface is being accomplished(e.g., delivering neuromodulation to the brain and/or sensing parametersfrom the brain). The device 252 shown in FIG. 23B is provided with EEGelectrodes 254 that can be used in acquiring an EEG. The device 252 isprovided with an active RFID controller 256. The device 252 is furtherprovided with a first transmitter antenna coil 262 located so that it ispositionable over the first receiver antenna 244 in the channel 100 anda second transmitter antenna coil 264 located so that it is positionableover the second receiver antenna 246 in the channel. The RFID capabilityis likely to be especially useful when the same channel 100 is beingused for multiple applications (e.g., for delivering neuromodulation andsensing), for example, by providing information about the relativepositions of the neuromodulation source and the channel or the innerlumens 180 provided in the channel and/or about the relative positionsof the channel and/or inner lumens and EEG electrodes.

Another variation of a transcranial channel is shown in FIG. 24, wherethe channel 100 is provided with an extracranial extension 300. In FIG.24, the extracranial extension 300 is associated with one transcranialchannel 100, although it will be apparent to those skilled in the artthat more channels may be used with the extension. The extension 300 hasa first portion 302 having dimensions designed to substantially coverand/or partially overlap the area of the skull 20 in which the channels100 are positioned and to lie between the scalp 12 and the skull 20. Theextension has a second portion 304 with a first end 306 and a second end308. The first end 306 of the second portion 304 may be connected to thefirst portion 302 of the extension and effectively continues the channelextracranially (e.g., if the channel is being used for conduction ofcurrent by ion conduction, the first portion 302 may have an inner lumenfilled with saline solution or fillable with an ion-permeablesubstance). The second end 308 of the second portion 304 may be routedpercutaneously or subcutaneously to another location in the body, e.g.,another location on the head or a location on the neck or shoulder.

The extracranial extension 300 thus permits the source ofneuromodulation, or the equipment for obtaining a measurement, to beplaced near the second end 308 of the second portion 304 of theextension rather than in the vicinity of the channel(s) 100, adding tothe flexibility of the skull/brain interface. The extension also mayincrease the cosmesis or aesthetics of the particular application of thechannel(s) from the perspective of the patient and therefore may makethe application(s) more popular with patients.

In still other variations, and with reference now to FIGS. 25A and 25B,one or more transcranial channels 100 may be provided for direct currentneuromodulation (e.g., polarization or stimulation) in combination withone or more deep brain or transparenchymal channels 310 (only a singletransparenchymal channel is shown in FIGS. 25A and 25B).

The transparenchymal channel 310 may be formed from a soft material suchas silicone and provided with an inner lumen 320. One or more stiffeningelements (not shown), such as a coil formed from metallic ornon-metallic materials, may be provided in or around thetransparenchymal channel inner lumen 320 to help maintain the patency ofthe lumen without comprising to any great extent the flexibility or“floppiness” of the transparenchymal channel. Alternatively, a thin coilof wire may be embedded in the transparenchymal channel 310 to encourageeach structure to remain patent and in the desired shape. Thetransparenchymal channel inner lumen 320 may be fillable with salinesolution or another ion-permeable substance.

In another variation, at least the side of the transparenchymal channel310 that is intended to contact the brain may be formed substantiallyfrom a soft, flexible ion-permeable material. This variation of atransparenchymal channel 310 may be designed for insertion into a brainsulcus.

In still another variation, a combination of a transcranial channel 100and a transparenchymal channel 310 may be provided as a single unit,characterized entirely by ion-permeability or having a contiguousinterior cavity that is ion-permeable or fillable with an ion-permeablesubstance. The dimensions of the combination of this variation should besufficient to allow sufficient slack, after implant, between theproximal end 106 of the transcranial channel 100 at the skull and thetransparenchymal channel 310 in the brain parenchyma or resting in asulcus of the brain, to accommodate movement of the brain inside theskull.

The transparenchymal channel(s) 310 may be used to deliver DCstimulation to target structures in the interior of the brain whileavoiding the potential complications that would otherwise be presentedby the electrode-to-tissue interface if a conventional deep brainelectrode were used. A transparenchymal channel 310 may be implantedinto the brain using techniques similar to those used by those skilledin the art to implant conventional deep brain electrodes for pulsatileelectrical stimulation. Alternatively, in the case of the variationwhere the transparenchymal channel 310 is substantially ion-permeable onthe side intended to contact the brain, the transparenchymal channel 310may be inserted into a sulcus of the brain.

With reference to FIG. 25A, the transparenchymal channel 310 may be usedin conjunction with the transcranial channels 100 to facilitate deepbrain stimulation without requiring the transparenchymal channel to becoupled mechanically to the dura mater 312 or the skull 20.

A collector 314 is associated with the transparenchymal channel(s) 310and designed to be implanted in the epidural space 316, i.e., betweenthe inner layer 40 of the skull 20 and the dura mater 312 or,alternatively, completely under the dura mater 312.

The collector 314 may be formed from a soft material such as siliconeand provided with an inner lumen 318. One or more stiffening elements(not shown), such as formed from metallic or non-metallic materials, maybe provided in or around the collector inner lumen 318 to help maintainthe patency of the lumen without comprising to any great extent theflexibility or “floppiness” of the collector. Alternatively, a thin coilof wire may be embedded in the collector 314 to encourage each structureto remain patent and in the desired shape. The collector 314 also may befillable with saline solution or another ion-permeable substance.

A variation involving the combination of a transcranial channel 100 anda transparenchymal channel 310 without a collector for application of DCstimulation is illustrated in FIG. 25B. The transcranial channel 100 hasan interior cavity 104 that is contiguous with the inner lumen 320 ofthe transparenchymal channel 310. In this variation, care should betaken when the transparenchymal channel is implanted to ensure thatthere is enough slack in transparenchymal channel to guard against itmoving, slicing, or pulling out of the brain as the brain shifts in theskull.

Deployment/Implantation of Transcranial Channels

In one variation, and referring now to FIG. 26, a transcranial channel100 may be implanted in a patient's skull by making an incision in thescalp 12 over or near the target region 24 of the brain to whichneuromodulation is to be applied or from which a signal is to beacquired or heat is to be transferred. A craniotomy may be performed ifthe entire skull is to be breached by the channel(s) (e.g., formation ofa burr hole 400) to remove a portion of the skull matching thedimensions of, or slightly greater than the dimensions of, theparticular channel(s) to be implanted. If the transcranial channel isone that is intended to be used without entirely breaching the skull, acraniectomy may be performed to remove a portion of the skull sufficientto allow placement of the channel. The surgeon can insert the channel(s)100 with gloved fingers or with an appropriate instrument such as aforceps.

If the channel 100 is provided with ridges 162, then the channel can betwisted or torqued while it is being inserted to help anchor the channelin the hole. Optionally, after the channel 100 is in the desiredposition, any open space between the skull 20 and the exterior of thechannel 100 can be filled with a glue or cement to secure the channeland to minimize the possible routes for infection of the brain. PMMA orpoly(methyl methylacrylate) is a common bone-compatible material thatcan be used for securing the channels 100. If the channel 100 isprovided with additional means for affixing it to the skull, forexample, screw holes 168, the channel 100 then is screwed into place inthe skull 20.

After all the steps to position the channel or channels 100 arecompleted, if the channels 100 are intended to be put to use in anapplication immediately, the channels may be flushed or purged withsaline. Optionally, the interior cavities 104 (or inner lumens 180 ifprovided) may be filled or partially filled with something: for example,a substance such as porous silicone, porous polyurethanes, or hydrogels;or porous masses constructed by sintering together particles of anonporous polymer such polyurethanes, polytetrafluoroethlene,polyetheretherketones, polyesters, polyamides (e.g., nylon); or a spongeor sponge-like substance infiltrated with a nonproliferative agent suchas bone morphogenic proteins, ciliary neurotrophic factor, ribavirin,sirolimus, mycophenolate, mofetil, azathioprine, paclitaxel,cyclophosphamide, or atomic silver to discourage cell proliferation andtissue growth into the channel.

The scalp 12 is then positioned over the channel proximal end(s) 106,and any incision is closed.

Next, the external equipment or devices necessary to carry out theintended application(s) for the channels 100 is brought in proximity tothe location of the channels in the skull 20. (It will be appreciated bythose with skill in the art that a given channel 100 may be used toprovide a skull/brain interface for more than one application, forexample, conducting a source of DC stimulation to a target area of thebrain and conducting signals from the brain out to the exterior of theskull for measurement, as for an EEG.)

Deployment/Implantation of Cannula-Like Transcranial Channel(s) withDilators

In another variation, a transcranial channel 100 having a lengthapproximating the thickness of the skull and an overall width much lessthan the length, e.g., a small bore, cannula-like transcranial channelas described with reference to FIGS. 16A-17C, may be implanted in apatient's skull according to the following method. A very small opening(on the order of the diameter of a hypodermic needle) is made in thescalp. The opening may be formed with a drill, needle, or otherappropriate instrument, and may terminate at the skull or may extendadditionally all the way through the thickness of the skull or only partway through the thickness of the skull, e.g., through about 90% of thethickness of the skull. A dilator is inserted into the scalp opening toincrease the size of the opening. If the scalp opening thus increased insize is large enough to accommodate the small bore transcranial channel,then the practitioner may next insert a retractor into the scalp openingto hold it open. A hole sufficiently large to accommodate the small boretranscranial channel may then be made in the skull with a drill or otherappropriate instrument, or if a hole was previously made it may beenlarged to accommodate the channel. The practitioner may then insertthe channel into the skull. The retractor and dilator are subsequentlyremoved, leaving the channel in place in the skull. If deemed necessaryor prudent, the proximal end of the channel may be trimmed to be flushwith the exterior surface of the skull after insertion and/or afterremoval of the retractor and dilator.

The channel(s) may be flushed with saline and, optionally, the interiorcavities thereof may be filled with a substance such as porous silicone,porous polyurethanes, saline solution, hydrogels, or porous massesconstructed by sintering together particles of a nonporous polymer suchpolyurethanes, polytetrafluoroethlene, polyetheretherketones,polyesters, polyamides (e.g., nylon).

The wound may be closed by means such as tape or glue, avoiding the needfor sutures and resulting in little or only moderate scarring. It isbelieved that this variation of a method for deploying small boretranscranial channels may be accomplished with minimal or localanesthesia and perhaps even with minimal disruption of the skin andscalp tissue overlaying the skull at the intended channel location,minimizing the complexity and invasiveness of the procedure.

After the channel(s) is/are inserted and the wound closed, the externalequipment or devices necessary to carry out the intended application(s)for the channel(s) may be brought in proximity to the channels and theapplication(s) may be commenced.

In still other variations of a method for inserting a small boretranscranial channel into the skull, multiple dilators may be used, oneafter another, to gradually expand the pin prick scalp opening to adegree sufficient to accommodate the channel. The “METRX X-TUBERETRACTION SYSTEM” available from Medtronic, Inc. is one system offeringa series of increasing diameter dilators with which this method may beaccomplished.

Identifying Where to Locate a Skull/Brain Interface (Aperture orChannel) Targeting with Evoked Responses

The skull/brain interfaces described herein, for example, the apertureinterfaces and the channel interfaces, desirably improve the ability tofocus neuromodulation (e.g., DC stimulation) in the brain better than ispossible without the interfaces. Of course, it is important to put theinterfaces where they will provide optimum focusing. One method foridentifying the areas of the brain on which the skull/brain interfacesare to focus involves using some form of evoked response or evokedresponses to localize or map out an area to be modulated (e.g., treated)or from which signals are to be sensed. The responses may be evoked fromregions that are candidates for treatment or monitoring. Alternatively,responses may be evoked from regions that are believed to be somehowassociated, directly or indirectly, with regions that are candidates fortreatment or monitoring (for example, via neural circuits or pathways).

One method of obtaining the evoked responses uses transcranial magneticstimulation (TMS). As described previously, TMS involves bringing thecoil of a magnet near the head and energizing it by rapidly discharginga capacitor, which creates a rapidly-changing current in the coilwindings. This rapidly-changing current sets up a magnetic field at aright angle to the plane of the coil. The magnetic field penetrates theskin and the skull to the brain and induces a current tangential to theskull. The current influences the activity of the neurons. TMS can beapplied on a single-pulse or paired-pulse basis, or repetitively (rTMS).

TMS may be used to evaluate where to locate a skull/brain interface orinterfaces by stimulating regions in an effort to evoke responses. Theevoked response sought might be a muscle twitch in a specific muscle orother reaction in a specific anatomical location. For example, in aperson with damage to the primary motor cortex caused by a stroke, TMSmay evoke a weakened muscle twitch when applied to the one area ascompared to a regular-strength muscle twitch in other areas. Theattenuated muscle response in the one area may suggest that that area isthe damaged area and therefore the area over which the skull/braininterface(s) should be located. Alternatively, a person who has suffereda stroke may exhibit a weakness in his left hand, which is controlled bythe right side of the patient's brain. TMS may be used to try andidentified the damaged or lesioned region on the right side of thebrain. TMS may also be used to identify the corresponding undamagedregion on the left side of the brain, which controls the right hand, soas to identify an area at which to introduce a skull/brain interface,based on the theory that stimulation therapy (e.g., inhibitorystimulation) delivered to the opposite, undamaged side of the brainmight improve the patient's ability to control or strengthen hisimpaired hand. In still another example, a region of the brain that isbelieved to be associated with a certain neurological function, such aslanguage processing or vision, may be identified by applying TMS atvarious locations on the skull and looking for a change in theneurological function, such as improved speech or vision or impairedspeech or vision. One or more skull/brain interfaces subsequently may beprovided at the areas so identified.

Other Aids for Locating Sites for Skull/Brain Interfaces Alternative toTraditional Stereotaxy

Stereotaxy is commonly used in neurosurgery and neurological research tolocate points within the brain using an external, three-dimensionalframe of reference (usually based on the Cartesian coordinate system).It is typically a relatively elaborate process, especially when itinvolves mounting a frame on the patient and attaching the frame withone or more skull pins. It is most often relied upon when targets withinthe brain are to be precisely targeted as, for example, in placingelectrodes on deep brain leads in or near particular brain structures,such as the subthalmic nucleus (STN).

While stereotaxy could be used to identify regions of the brain overwhich skull/brain interfaces are to be formed, less elaborate methodsalso may be sufficient under the particular circumstances. For example,an overlay that can be written upon or otherwise marked, such as asticker or a sheet of plastic with temporary adhesive backing, can belaid over a section of the head to facilitate locating the site or sitesat which skull/brain interfaces are to be provided. The overlay may havea feature that allows it to be oriented on the head with respect to someanatomical marker, such as the patient's ear. The overlay may includeone or more pre-marked locations corresponding to possible sites forskull/brain interfaces, so that when the overlay is placed on thepatient's head, the surgeon can choose from among several options forlocations. Additionally or alternatively, the overlay may have space onwhich the surgeon can mark his or her own choice of sites for theinterface(s).

A form of a low-resolution stereotactic assembly may be provided aloneor together with an overlay to aid in identifying the locations at whichskull/brain interfaces are to be placed. Referring now to FIG. 27, alow-resolution stereotactic assembly 274 is shown provided with a body275 having a skull/brain interface template 276 comprising a pluralityof holes 278 formed in the body 275. The holes 278 are shown spacedapart from one another by a distance, d. Although in FIG. 27, thedimensions of the holes 278 and the distance, d, between the holes shownare uniform, it will be apparent to one with skill in the art that holesof different sizes and shapes might be provided, as well as holes with avariety of different sizes and shapes, and that the distances, d,between the holes also may vary.

The template 276 may formed integrally with the body 275 or provided asa separate component. If the low-resolution stereotactic assembly 274 isconfigured with the body 275 and template 276 as separate components,then a plurality of templates 276 with different patterns of holes 278and distances, d, may be made available for use with the assembly 274.Different templates can be designed for different intended uses of theskull/brain interfaces (e.g., DC stimulation of a large area such asdorsolateral prefrontal cortex, DC stimulation of a small area such asan epileptic focus, measurement of signals from the brain, etc.). Thelow-resolution stereotactic assembly 274 also may be provided withblanks that can be formed into customized templates for a particularpatient, for a particular intended use for a skull/brain interface, oraccording to the surgeon's preference. The templates 276 may be used toguide marking the scalp for location of skull/brain interfaces, whereincisions in the scalp should be made, and/or where a drill ordilator(s) should be positioned for forming apertures or installingchannels for the skull/brain interfaces described herein.

The low-resolution stereotactic assembly 274 is shown in FIG. 27 withthe options of an orienting feature 280 to aid in orienting the assembly274 on the patient's head with reference to an anatomical marker (thepatient's ear in the case of FIG. 27) and a securing feature 282 to holdthe assembly 274 on the patient's head (a strap in the case of FIG. #).In addition to or in lieu of one or more orienting features 280, thelow-resolution stereotactic assembly 274 may be provided with anadhesive that permits the assembly 274 to be temporarily adhered to thepatient's head.

Skull/Brain Interface Kits

One or more kits may be provided with components for facilitating theskull/brain interfaces described herein, both in the form of aperturesand channels. A kit may contain items such as the overlay and/orlow-resolution stereotactic assembly 274 described above.

A kit may also be configured to include a plurality of channels ofvarious sizes, shapes and lengths. The lengths may be selected toaccommodate skull thicknesses that vary from patient to patient, as wellas surgeon preferences for the extent to which a given channel willtraverse the thickness of the skull (e.g., all the way through (100% ofthe skull thickness) or partially through (such as 90% of the skullthickness). Additionally, channels having a plurality of inner lumensmay be provided with inner lumens of different lengths.

A kit further may be configured to contain different types of channels,for example, plugs, cannula-like channels, and/or multi-lumen channels,etc. In this fashion, a kit may be customized for a particularapplication of a skull/brain interface.

In still other variations, a kit may be provided with a scalp electrodepad 45 or a scalp electrode pad assembly 46 as described herein withreference to FIGS. 3A and 3B.

In yet other variations, a kit may be provided that includes astimulator to be used with a skull/brain interface alone or togetherwith an accessory on which the stimulator or the electronics of thestimulator can be or is already mounted. Because the apertures or otherfenestration or channels will facilitate focusing of the stimulationfrom the source to the target areas of the brain, the positioning of thestimulation source in the headpiece relative to the skull/braininterface does not have to be especially precise. For example, awashable hat or headpiece may be provided with a feature (such as apouch) that allows it to accommodate a source of DC stimulation, and aDC stimulation that fits into the hat may or may not also be provided.The entire stimulation source may be selectively insertable into thehat, or just the electronics for the stimulation source may beremovable. Alternatively, the stimulation source may be built into ahelmet for use with skull/brain interfaces for particular indications orapplications. For example, when a skull/brain interface is intended tobe used for a performance-enhancing application as describedhereinbelow, the stimulator or just at portion of the stimulation source(e.g., the electrode through which stimulation is delivered), may belocated in a pilot's helmet for applications designed to improve visualacuity or alertness.

Gauging Skull Thickness

Installation of a skull/brain interface may be facilitated by a featurethat allows the thickness of a patient's skull to be measured before anaperture is formed or a channel installed, and/or while an aperture isbeing formed, as with a drill. Ultrasonic reflections from the interfacebetween the inner table and the cranial cavity can be analyzed in orderto determine when a desired thickness of the skull has been traversed. Askull/brain interface kit may be provided with a tool or other devicefor measuring the thickness of a patient's skull at various locations asan aid for determining how deep to drill to form an aperture or aperturefor receiving a channel, how far to insert a dilator, and/or which ofseveral available channels to use (e.g., from among channels of avariety of lengths). In one variation, the tool may be an ultrasoundtool. Alternatively, a drill may be provided with an ultrasonictransducer at the tip that allows the thickness of the skull forward ofthe drill to be continuously monitored during the drilling. For example,if a surgeon wishes to install a channel so that it traverses about 90%of the thickness of the skull in a particular region (i.e., so thechannel extends almost all the way but not entirely through the skull),then the ultrasonic transducer may be relied upon to indicate to thesurgeon when the drill tip is about 10% of the way away (or so manymillimeters away) from breaching the skull and entering into the cranialcavity.

Deployment/Implantation of Transcranial Channels with ExtracranialExtension(s)

In yet another variation, one or more transcranial channels togetherwith an extracranial extension 300, as such a combination is describedabove in connection with FIG. 24, may be implanted in a patient.

The first and second portions 302 and 304 of an extracranial extension300 may be implanted in the patient under the skin and positioned sothat the first portion 302 can be located over the proximal end(s) 106of the channels 100, the first end 306 of the second portion 304connected to the first portion 302, and the second end 308 of the secondportion 304 is positioned to interface with external equipment or adevice with which to carry out the intended application (e.g.,delivering neuromodulation through the extracranial extension 300 andchannels 100, or measuring signals from the brain through the channelsand the extension).

One position for the second end 308 of the second portion 304 might beat the base of the skull, neck, chest, or shoulder of the patient.

The extracranial extension 300 may be implanted before, concurrentlywith, or after implanting the channel(s) 100, and may be routed to thedesired position for the second end 308 of the second portion 304 usingtechniques similar to those used by those skilled in the art to tunneldeep brain lead extensions for pulsatile electrical stimulation.

Any incisions or wounds created by reason of insertion of the channel(s)100 and the positioning of the extracranial extension 300 and the secondend 308 of the second portion 304 of the extracranial extension are thenclosed. Thereafter, the external equipment or devices necessary to carryout the intended application(s) for the channel(s) may be brought inproximity to the second end 308 and the application(s) may be commenced.

Deployment/Implantation of Transcranial Channel(s) with TransparenchymalChannel(s)

In another variation, one or more transcranial channels may be implantedin a patient's skull together with one or more transparenchymal channels310 as such a combination is described in connection with FIGS. 25A and25B, above.

Each transparenchymal channel 310 may be implanted using techniquessimilar to or the same as those used in implanting conventional deepbrain electrodes (e.g., using frame-based or frameless stereotacticnavigation, etc.). To facilitate these implant techniques, a removablestylet (not shown) may be placed within the ion-permeable lumen of thetransparenchymal channel 310 or within a dedicated lumen (not shown)that is generally parallel to the ion-permeable lumen. A collector 314(if used), may be coupled to the transparenchymal channel 310 andpositioned to lie in the epidural space 316, between the inner layer 40of the skull 20 and the dura mater 312 or, alternatively, completelyunder the dura mater 312. One or more transcranial channels 100 may thenbe implanted in the skull 20 over the transparenchymal channel(s) 310and collector(s) 314 (if used).

Alternatively, a transparenchymal channel 310 may be provided that isentirely ion-permeable, at least on the side thereof that will be incontact with the brain, and placed in a sulcus of the brain. Thisvariation may allow DC stimulation to be conducted to tissue located ina sulcus, with little loss of stimulation amplitude as compared tostimulation delivered at the gyral crown.

In still another variation, the transcranial channel 100 andtransparenchymal channel 310 may be implanted simultaneously as, forexample, when the transcranial channel 100 and transparenchymal channel310 are provided as a single unit of ion-permeable material. In thisvariation, care must be taken to ensure that there is enough slack leftbetween the proximal end of the transcranial channel at the skull andthe transparenchymal channel in the brain, to allow for some movement ofthe brain within the skull.

Any incisions or wounds created by reason of insertion of the channel(s)100 are then closed. Thereafter, the external equipment or devicesnecessary to carry out the intended application(s) for the channel(s)may be brought in proximity to the channels and the application(s) maybe commenced.

Using Transcranial Channels for DC Stimulation

Referring again to FIG. 2, for DC stimulation of a target area 24,either a conductive gel 14 or a saline-filled sponge (not shown) isapplied to the exterior of the scalp 12 over the transcranial channel(s)100. A first pole 10 of a current source can be brought in contact withthe conductive gel 14 or saline-soaked sponge, and neuromodulation(e.g., polarization or stimulation) of the target area 24 may becommenced.

FIGS. 28A and 28B represent the results of a finite element model (FEM)analysis of the focality of DC stimulation before and after formation ofa skull/brain interface (with a channel or simply with an aperture). Theshading represents the relative magnitude of the electric field, withmore concentrated shading corresponding to higher field magnitude. Thearrows represent the direction and magnitude of current flow. The FEMsolution (axisymmetric around the vertical axis) is provided using afive-sphere model taking into account skull layers: (1) sphere radii7.8, 8.2, 8.3, 8.6, 8.7, and 9.2 cm respectively for the outer surfacesof brain, cerebrospinal fluid, inner compact bone, spongiform bone,outer compact bone, and scalp; and (2) conductivity of 0.45, 1.35,0.0056, 0.45, 0.0056, and 0.45 S/m respectively for brain, cerebrospinalfluid, inner compact bone, spongiform bone, outer compact bone, andscalp. Stimulation was modeled as 9 Volt transcranial DC stimulation,applied between the electrode shown and an electrode applied at theopposite pole of the sphere (not shown). (It is noted that Bikson et al.have reported that 40 V/m is sufficient for significant neuromodulation(BIKSON et al., “Effects of Uniform Extracellular DC Electric Field OnExcitability In Rat Hippocampal Slices In Vitro,” J. Physiol. 557:175-190 (2004).)

Non-Pulsatile and Near-DC Electrical Stimulation Using TranscranialChannels

Non-pulsatile and near-DC electrical stimulation of a target area in thebrain may be carried out through one or more transcranial channels 100in the same manner as DC stimulation may be carried out. That is, eithera conductive gel 14 or a saline-filled sponge (not shown) is applied tothe exterior of the scalp 12 over one or more implanted transcranialchannels 100, which are located over a target area 24 of the brain. Afirst pole 10 of a current source can be brought in contact with theconductive gel 14 or saline-soaked sponge, and neuromodulation (e.g.,polarization or stimulation) of the target area 24 may be commenced withnon-pulsatile or near-DC waveforms, such as large amplitude waveforms,slowly varying oscillatory waveforms, and low frequency sine waves.

Pulsatile and AC Stimulation Using Transcranial Channels

As discussed previously herein, pulsatile and AC stimulation waveformsmay be delivered through the electrode-tissue interface with goodfocality and few ill effects (provided that the waveforms used satisfycharge-density-per-phase limitations and that charge balancing ismaintained). Nevertheless, and while transcranial channels are notnecessary for focal delivery of these types of waveforms, focal deliverymay still be facilitated by these devices. More particularly, in certainscenarios, scalp application of pulsatile and AC stimulation waveformsthrough a skull/brain interface as provided by a transcranial channel100 may be deemed to be safer and less expensive than, for example,delivery of similar waveforms using an implanted pulse generator orneurostimulator.

Responsive or Feedback-Controlled Stimulation

In one variation, a device or system used with a skull/brain interfacemay be configured to have both stimulation and sensing capabilities. Thesensing capability may include one or more electrodes that can sensephysiological signals from the brain that are understood to correspondto, for example, a characteristic of a disorder or neurological state.The system may be configured to relate the stimulation delivered to thephysiological signal(s) sensed in some manner, as in a closed-loopfeedback arrangement. In one variation, the system may be preprogrammedto respond with stimulation in a particular form or characterized byparticular parameters whenever a predetermined physiological signal orpattern of signals is sensed by the sensors (i.e., responsivestimulation). A form of control law or control laws additionally may beimplemented in the system to modify the stimulation based on changes inthe sensed signals. the stimulation device may be additionally providedwith sensing electrodes, and the electrodes used to detect sleep stages,such as slow-wave sleep, or other neurological states.

Using Transcranial Channels for Iontophoresis

Transcranial channels 100 may be used to facilitate iontophoresisthrough the skull, allowing delivery of ions or charged molecules ofbiologically-active agents into the intracranial space. As noted above,these agents may include, but are not limited to, glutamate,acetylcholine, valproate, aspartate, gamma amino butyrate,adrenocorticotropic hormone (ACTH), cortisol, beta endorphin, andserotonin. Scalp electrodes may be provided and coated or infiltratedwith one or more of the agents intended for delivery to a target area ortarget areas of the brain. These agents may also be mixed with aconductive gel or saline solution, or simply applied to the region ofthe scalp between the stimulating electrode and the transcranial channel100.

Using Transcranial Channels to Stimulate with Light

Transcranial channels 100 may be used to conduct light for modulatingthe activity of neural tissue. More particularly, and by way of example,variations of the channels 100 may be constructed partially orsubstantially of material that is transparent, essentially transparent,semi-transparent, or selectively transparent to certain selectedwavelengths of light. Since the external light directed at the skullordinarily would be significantly diffused and attenuated before any ofit reached the brain, use of the channels 100 as a conduit for lightapplied at the scalp would facilitate optical neuromodulation. It willbe apparent to those with skill in the art that the same channel couldbe used to conduct light as well as electrical stimulation, such as DCstimulation, to target areas of the brain.

Scalp EEG Using Transcranial Channels

Use of one or more transcranial channels 100 in measuring signals fromthe brain, may reduce the blurring of the signals that otherwise occursin scalp EEG without the channels (i.e., scalp EEG acquired through therelatively nonconductive skull). Comparable to the manner in which atranscranial channel will reduce dispersal of current that otherwiseoccurs in the application of tDCS without a channel, the net electricalfield and current produced by neural activity will be more faithfullyreproduced on the surface of the scalp using one or more channels, wherethey then can be measured using conventional scalp EEG equipment.

Moreover, a plurality of transcranial channels 100 implanted above oneor more regions of interest 24 in the brain, or a single channel 100with a plurality of inner lumens 180 or a longitudinally divided lumen,may be used to more faithfully reproduce on the scalp the spatialdistribution of electrical fields and currents produced by neuralactivity in those regions, and this signal may be measured by aconventional, multi-channel scalp EEG. The better quality, higherresolution EEG signals may be more conducive than are conventionallyobtained signals for applications such as using the signals forprosthetic control.

It will be appreciated by those with skill in the art that a singletranscranial channel 100 may be used for dual applications, for example,conduction of a source of DC stimulation and conduction of signals forEEG measurement. Because many EEG signals of interest are time-varyingsignals, they may be separated by well-known techniques from artifactsthat may be induced by the DC stimulation.

EEG electrodes may be placed against the scalp in the conventionalmanner, under the DC stimulation current electrode. Alternatively, theEEG electrodes may be constructed as part of the DC current electrodeassembly. Still another alternative would be to use an electrodesimultaneously for DC stimulation and as an EEG sensor, usingamplification and signal separation techniques as are well known in theart. In one variation, the EEG signal may be processed to yield ameasurement of epileptiform or seizure activity, and this measurementthen used to modulate the amplitude of inhibitory transcranial DCstimulation, in an effort to provide optimal reduction of epileptiformor seizure activity.

Impedance Plethysmography and Tomography Using Transcranial Channels

A transcranial channel 100 provides a known path through the otherwiserelatively nonconductive skull; thus it will be appreciated by thoseskilled in the art that a channel 100 can facilitate measurement ofbrain perfusion changes using electrical impedance plethysmography. Itwill further be appreciated that use of a plurality of transcranialchannels 100 may facilitate electrical impedance tomography based onsimilar principles.

Optical Imaging and Tomography Using Transcranial Channels

As noted above, variations of transcranial channels 100 can beconstructed of materials that are transparent, essentially transparent,semi-transparent, or selectively transparent to selected wavelengths oflight. Without a channel in place, the skull causes significantdiffusion and attenuation of light as well as electrical current. Byeliminating the scattering that would otherwise be caused by the skullin a selected region and by providing a defined path for direct lighttransmission through the skull, a transparent, essentially transparent,semi-transparent, or selectively transparent transcranial channel 100may facilitate optical measurement or optical tomography applied at thescalp.

It will be appreciated by those with skill in the art that thesevariations of transcranial channels may also be ion-conductive, allowingone channel to be used to facilitate both optical and electricalneurosensing.

Use of a Transcranial Channel to Cool the Brain

A transcranial channel 100 designed for the purpose of providing askull/brain interface through which heat can be withdrawn from theinterior of the skull, as described in connection with FIGS. 18A and 18Babove, can be used to cool a target area 24 of the brain, such as anepileptic focus. In this variation, after the channel is implanted andany wound closed, a heat-absorbing or cooling device 224, such as athermoelectric device, a device or chamber through which a salinesolution is pumped, or an ice pack, etc. may be brought in proximity tothe thermally conductive element(s) of the channel 100 to accomplish thetransfer of heat from, or cooling of, the target area. Theheat-absorbing or cooling device may be selectively activated orselectively brought into the vicinity of the proximal end 106 of thechannel, for example, whenever a sensor detects a temperature in excessof a predetermined limit or limits. As is the case with any of themethods described herein, multiple channels 100 may be provided in orderto accomplish the energy transfer.

In another variation of this method, energy may be transferred from asource external to the skull to the interior of the skull, such as in ahigh intensity focused ultrasound (“HIFU”) application using, forexample, the transcranial channel 100 described in connection with FIGS.19 and 20 above. The skull/brain interface provided by a channel 100that is substantially transparent to ultrasound will tend to preventdistortion of the ultrasound by the skull bone and help to focus theultrasound more precisely on the target area(s) 24 of the brain. Thistechnique may be used, for example, to ablate brain tissue or toprecisely create lesions in the brain without resorting to more invasivebrain surgery procedures.

In some embodiments, imaging such as computed tomography (CT) scans,Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI),and functional magnetic resonance imaging (fMRI), may be used to helpdetermine where to place the transcranial channel or channels, based onthe location, condition and/or nature of various brain structures.

Additional Aspects of Stimulation Used with the Skull/Brain Interfaces

When a skull/brain interface is used in a system for delivering a formof stimulation to the patient to encourage neuromodulation (e.g., toexcite or inhibit neural activity), the system may be provided withvarious features to enhance control of the stimulation, potentiallyimprove the results of certain types of stimulation or stimulationdelivered for certain indications, and to facilitate situating astimulation source in the vicinity of the skull/brain interface (or inthe vicinity of an end of an extracranial extension connected to askull/brain interface). Some of these features are described in moredetail hereinbelow.

Limited Patient-Controlled Stimulation in a Portable Stimulator

A stimulation source used with the skull/brain interfaces describedherein desirably is portable so that the source can be used when thepatient is variously situated, and not limited to use, for example, onlywhen a patient is in an operating room or clinician's office. Astimulation source may be configurable so that it fits into a hat orhelmet, as described previously herein.

In some variations, the stimulation source may be controllable orpartially controllable by a patient or a caregiver. A stimulation sourcemay be configured so that the patient or caregiver may control apredetermined subset of the parameters that define and/or controlgeneration of the stimulation, such as the relative strength of thestimulation. Alternatively, all of stimulation parameters may be fixedbut the patient may be provided with limited discretion to decide whenstimulation is delivered or how often it is delivered up to some maximumor below some threshold (e.g., no more than 10 doses of electricalstimulation or a drug per 24-hour period, no more often than one doseevery 30 seconds, etc.) Similarly, the stimulation source and/orskull/brain interface may be configured to disallow further stimulationor doses of stimulation device when a prescribed amount is exceeded or aprescription expires.

In other variations, a wireless or wired remote may be provided tooperate a stimulation or other neuromodulation source. For example, aremote may be used to operate a hat-mounted or head-mounted stimulator.The remote control may enable, for example, patient-controlledstimulation. In an embodiment, the remote control operations may beperformed as part of the operation of another device, such as a computersystem that stores and/or performs other operations on sensed data orcontrols or manages stimulation.

Current Control and Impedance Measurement

In one variation, a stimulator configured to provide stimulation toneural tissue via a transcranial channel may include acurrent-controlled stimulation source. The current-controlledstimulation source can be used to control therapy despite impedancevariations or changes in the electrode/scalp interface. Alternately, theimpedance of the stimulation path could be detected, for example betweenone stimulating electrode and another stimulating electrode of oppositepolarity, or between one stimulating electrode and a return electrode.If the impedance is not within an acceptable range, stimulation may beceased, attenuated, or otherwise modified, and/or the patient may bealerted.

Examples of Some Specific Indications for Skull/Brain Interfaces

Generally, it is intended that the skull/brain interfaces describedherein be used both in lieu of more invasive options (such as deep brainleads connected to implanted neurostimulators) and less invasive (butalso less focused) options such as transcutaneous electrical stimulationor DC stimulation delivered through the intact skull.

A number of indications for the skull/brain interfaces are identifiedthroughout this disclosure, such as diagnosis of, relief of the symptomsof, or reversal or repair of damage caused by, neurological dysfunctioncaused by neurological damage, neurologic disease, neurodegenerativeconditions and/or other conditions.

The neurological dysfunction may be related to, for example and not byway of limitation, epilepsy, movement disorders such as Parkinson'sdisease, Huntington's disease, essential tremor, stroke, traumatic braininjury, cerebral palsy, multiple sclerosis, Alzheimer's disease,dementia (including frontotemporal dementia and multi-infarct dementia),memory disorders, stroke rehabilitation, aphasia, mild cognitivedisorders, depression, bipolar disorder, anxiety disorders,obsessive-compulsive disorders, eating disorders, Tourette's syndrome,restless leg syndrome, coma (especially affecting the frontal lobe),schizophrenia, post-traumatic stress syndrome or other neuropsychiatricaffect disorders, learning disorders (includingattention-deficit-hyperactivity disorders), autism, speech disorders,auditory or hearing disorders (e.g., tinnitus), craving and addictivedisorders, sleep disorders (including narcolepsy and excessive daytimesleepiness disorder), headaches including migraine headaches, tensionheadaches and cluster headaches, and other dysfunctions caused by braininjury or characterized by chronic pain.

More specific examples of some contemplated indications for theskull/brain interfaces and/or methods for implementing the same aredescribed hereinbelow.

Sleep Staging and Selective Stimulation

Neurological states occurring during sleep are of interest with respectto a variety of neurological disorders and conditions (for example,epileptic seizures may occur more or less frequently during certainsleep stages in certain patients, certain cognitive processes may bemore active during certain sleep stages than during wakefulness, etc.).

In one variation of a device or system to be used with a skull/braininterface as described herein, the system may be configured to havesensors in the form of electrodes to monitor a patient during sleep andto detect one or more stages of sleep, such as slow-wave sleep, or otherneurological states occurring during sleep. The device or system may befurther configured to use the monitored or sensed information to decidewhen to deliver stimulation or what parameters to use in generating ordelivering stimulation in a responsive or closed-loop feedback manner.For example, the monitored or detected information may be used by thesystem to apply stimulation selectively during one or more sleep stagesor when another neurological state is detected, such as a state that isbelieved to be involved in memory consolidation. The monitored ordetected information may also be used to vary stimulation deliveredbased on changes in the sensed information, such as delivering one formof stimulation when a first sleep stage manifests, and then different orno stimulation when the patient transitions to another sleep stage.

Performance-Enhancing Stimulation

In addition to being used for treating neurological disorders, it iscontemplated that the skull/brain interfaces described herein may beused together with a stimulation source and/or a device for measuringphysiological signals from the brain in an effort to enhance a patient'sperformance in one or more areas, such as visual acuity, memory, ormental alertness. Optionally, the stimulation and/or stimulationdetection system may be provided, as described above, in a pilot'shelmet or as temporarily positionable in a headpiece, to bring thesystem in the vicinity of the skull/brain interface(s).

Some examples of performance-enhancing indications are described in moredetail below.

Vision-Enhancing Indications

More particularly, it is anticipated that transcranial channels,apertures or fenestrations as disclosed herein may be used to facilitatethe effect of tDCS on the visual cortex or on desired part(s) of thevisual cortex. For example, anodal DC stimulation introduced through oneor more skull/brain interface to focus stimulation over the occipitalcortex is expected to reduce the threshold for preception of phosphenes.Conversely, cathodal tDCS delivered through one or more skull/braininterfaces located over the occipital cortex is expected to increase thethreshold for perception of phosphenes.

Memory-Enhancing Indications

It is envisioned that the transcranial channel(s) or aperture(s) orfenestration(s) disclosed herein may be used to facilitate the effect oftDCS on the DLPFC or other regions of the brain related to memoryfunction. For example, anodal DC stimulation introduced through askull/brain interface or interface(s) deployed to cause neuromodulationof the dorsolateral prefrontal cortex (DLPFC) is expected to increasethe accuracy with which a patient can perform a working memory task. Thesame anodal DC stimulation delivered with one or more skull/braininterfaces deployed at frontolateral locations during slow-wave sleep isexpected to increase retention of word pairs in a declarative memorytask.

Enhancing Verbal Fluency

It is envisioned that transcranial channel(s) or aperture(s) or otherfenestration(s) as disclosed in this application may be used tofacilitate the effect of tDCS on left prefrontal cortex or other regionsof the brain related to verbal fluency. For example, anodal tDCSdelivered through a skull/brain interface or interfaces to the leftprefrontal cortex is expected to increase verbal fluency, while cathodaltDCS delivered to the same location is expected to mildly decreaseverbal fluency.

Inhibition of Executive Function to Induce Creative or Savant State

It is envisioned that cathodal tDCS delivered to the prefrontal cortexor other regions of the brain understood to be responsible for executivefunction may be used to disinhibit creative functions or induce asavant-like state, and that transcranial channel(s), aperture(s), orfenestration as disclosed in this application may be used to facilitatethis effect of tDCS on prefrontal cortex or other regions of the brainrelated to executive function. Conversely, anodal tDCS may be used topotentiate (promote or strengthen) executive function and treat symptomsof autism.

Other performance-enhancing indications for skull/brain interfacesaccording to the invention with stimulation and stimulation/detectionsystems will be apparent to those with skill in the art.

Using DC Fields for Axonal Regrowth

It is envisioned that transcranial channel(s), aperture(s) or otherfenestration(s) as disclosed herein may be used as skull/braininterfaces for an electrical field source located outside the body, toproduce a controlled electrical field within or near tissue such as thebrain or other nervous tissue. It is known that DC electrical fields areknown to guide axonal growth and stem cell migration. Thus, thecontrolled electrical field induced through the interface(s) is expectedto potentiate, inhibit and/or direct axonal growth or regrowth, ordesirable migration of endogenous or exogenous cells within the tissue.

Using DC Stimulation for Cognitive Dysfunction as in Alzheimer's Disease

It is envisioned that transcranial channel(s), aperture(s) or otherfenestration(s) as disclosed herein may be used to improve workingmemory or cognitive function in, for example: cases of dementia, such asfrontotemporal dementia or multi-infarct dementia; cases of mildcognitive impairment; learning disorders; or other disorders affectingmemory and cognition. For example, anodal tDCS delivered through askull/brain interface or interfaces bilaterally over temporoparietalareas is expected to increase accuracy of a word recognition task inAlzheimer's disease patients.

Psychiatric Disorders (e.g., Schizophrenia and Bipolar Disorder)

Transcranial magnetic stimulation of the prefrontal cortex is currentlyunder study to treat such psychiatric disorders as schizophrenia andbipolar disorder. It is envisioned that transcranial channel(s),aperture(s) or fenestration(s) as disclosed herein may be used tofacilitate the effect of tDCS on cortical areas, such as the prefrontalcortex, related to these psychiatric disorders. A DC stimulation sourceand the skull/brain interfaces according to the invention may be usedalone or in combination with one or more deep brain elements, such asthe transparenchymal channels described hereinabove, to facilitatepenetration of the neuromodulatory effect to deeper brain structures,such as ventral striata, related to these psychiatric disorders.

Stimulation for Treating Coma Patients

It is envisioned that transcranial channel(s), aperture(s) orfenestration(s) as disclosed herein may be used to improve neurologicalfunction in, for example, cases of coma or cases of minimally-consciousstate (MCS). For example, anodal tDCS delivered through a skull/braininterface or interfaces over cortex is expected to increase neuralactivity in the stimulated region. A stimulation source, such as DCcurrent, and the skull/brain interfaces according to the invention mayalso be used alone or in combination with one or more deep brainelements, such as the transparenchymal channels described hereinabove,to facilitate penetration of the neuromodulatory effect to deeper brainstructures, such as intralaminar nuclei of the thalamus or tissuecomprising the reticular activating network, expected to influenceneurological arousal.

Tinnitus

It is anticipated that transcranial channel(s), aperture(s) orfenestration(s) as disclosed herein may be used to focus tDCS fortreatment of tinnitus. For example, anodal DC stimulation introducedthrough one or more skull/brain interfaces to focus stimulation over theleft temporoparietal area is expected to reduce the symptoms oftinnitus.

DC Stimulation for Language and Verbal Skills (e.g., Treatment forAphasia)

It is anticipated that transcranial channel(s), aperture(s) orfenestration(s) as disclosed herein may be used to focus tDCS fortreatments related to language or verbal performance. For example,anodal DC stimulation introduced through one or more skull/braininterface to focus stimulation over the left perisylvian area isexpected to enhance performance in normal patients whereas DCstimulation, such as cathodal DC stimulation, introduced over the leftfrontotemporal area is expected to result in improvement in languageperformance in patients with aphasia.

Stimulation for Treating Pain

Headaches

Headaches, for example migraine headaches, are believed to be in part adisorder of abnormal cortical excitability or abnormal corticalinhibition, and attempts to treat headache using TMS are beinginvestigated. Both tDCS and repetitive (1 Hz) electrical stimulationhave been shown in rats to modulate the velocity of cortical spreadingdepression, a phenomenon believed to be related to migraine. It isenvisioned that transcranial channel(s), aperture(s) or fenestration(s)as disclosed herein may be used to focus tDCS or repetitive electricalstimulation for modulating cortical excitability for treatment ofheadache, including migraine headache, tension headache, clusterheadache, and other types of headache.

Neuropathic Pain

It is envisioned that transcranial channel(s), aperture(s), or otherfenestration(s) as disclosed herein may be used to facilitate the effectof tDCS on primary motor cortex (M1), somatosensory cortex, DLPFC, orother regions of the brain related to pain and pain processing, in orderto treat pain disorders. Examples of pain disorders includepost-herpetic pain, phantom limb pain, failed back surgery syndrome(FBS), complex regional pain syndrome (CPRS), and neuropathic pain.

In one variation, channels, apertures, or fenestrations would be placedover multiple pain-related cortical regions, and stimulation may bedelivered to each region with less blurring and overlap than would occurin the absence of the channels, apertures or fenestrations.

In another variation, anodal DC stimulation introduced through one ormore skull/brain interface to focus stimulation over the primary motorcortex (M1) is expected to reduce pain due to fibromyalgia and traumaticspinal cord injury.

In an additional variation, cathodal tDCS delivered through askull/brain interface or interface(s) located over the somatosensorycortex is expected to reduce sensation of acute pain.

In a still other variation, anodal stimulation focused through askull/brain interface on the dorsolateral prefrontal cortex (DLPFC) isexpected to modulate a patient's emotional response to pain (such aspost-herpetic pain, phantom limb pain, failed back surgery syndrome,complex regional pain syndrome and neuropathic pain generally).

Autism

It is anticipated that transcranial channel(s), aperture(s) orfenestration(s) as disclosed herein may be used to focus tDCS fortreatments for autism. For example, anodic DC stimulation focusedthrough a skull/brain interface on the left frontotemporal cortex isexpected to benefit patients with autism or autistic symptoms.

Stimulation for Neuroprotection for Stroke

Stimulation of deep brain nuclei such as the fastigial nucleus isbelieved to yield neuroprotection against excitotoxic and ischemicinjury such as during stroke. It is envisioned that transcranialchannel(s), aperture(s) or other fenestration(s) as disclosed herein,used in conjunction with one or more transparenchymal channels asdescribed hereinabove, would facilitate use of transcranial directcurrent or non-DC transcranial electrical stimulation for this purpose.

Stimulation for Addictions and Cravings, and Involuntary orSemi-Voluntary Behaviors

tDCS delivered to left and right dorsolateral prefrontal cortex (DLPFC)has been shown to reduce cravings for smoking and food. It is envisionedthat channel(s), aperture(s) or fenestration(s) as disclosed herein maybe used to facilitate such effects of tDCS, in order to treat suchdisorders as addiction and obesity. Similarly, it is envisioned thatapplying DC stimulation through skull/brain interfaces will be effectivein managing or controlling other semi-voluntary or involuntary behaviorssuch as those characterizing obsessive-compulsive disorder andTourette's syndrome.

Stimulation for Addictions, Cravings, and Involuntary/Semi-VoluntaryBehaviors

TMS delivered to visual cortex has been shown to improve visual functionin amblyopia. It is envisioned that tDCS may be used to similar effect,and that channel(s), aperture(s) or fenestration(s) as disclosed hereinmay be used to facilitate such effects of tDCS, in order to treat suchdisorders as amblyopia.

Although the above systems, devices and methods have been described inthe context of transcranial channels, it is intended that theembodiments have useful application elsewhere in the body, for example,anywhere that neural tissue is shielded by tissue such as bone or avertebral disk. In one specific example, a channel may be placed througha vertebra or between two vertebrae, and used to facilitate spinal cordneuromodulation via an extraspinal or entirely extracorporealstimulation device.

The systems, devices and methods described herein may be useful in thediagnosis, symptom relief, reversal or repair of damage related toneurological trauma or neurodegenerative conditions, otherwise improvingpatient quality of life, and in enhancing performance in otherwisenormally-functioning patients.

The systems, devices and methods described herein may be used to detectelectrical activity from neurons or generate electrical activity inneurons using electrical neurostimulation in conjunction with anadjunctive or synergistic procedure, including but not limited to apharmacological therapy, an auditory or visual therapy or warning of theonset or imminent onset of an event or condition, a physical orbehavioral therapy, and a procedure to implant cells such as stem cells.

It will be appreciated that the above-disclosed and other features andfunctions, or alternatives thereof, may be desirably combined into manyother different systems or applications. It will also be appreciatedthat various presently unforeseen or unanticipated alternatives,modifications, variations or improvements therein may be subsequentlymade by those skilled in the art which are also intended to beencompassed by the following claims.

What is claimed is:
 1. A system for facilitating the delivery of a form of neuromodulation to, or the detecting of signals from, one or more target regions of a subject's brain, the system comprising: a transcranial channel configured for transcranial implant to extend between an outer layer of a skull and an inner layer of the skull, the transcranial channel having: a transcranial-channel proximal end having a proximal-end opening arranged to be oriented towards the outer layer of the skull; a transcranial channel distal end having a distal-end opening arranged to be oriented towards the first target region; and a transcranial inner lumen extending between the proximal-end opening and the distal-end opening and adapted to conduct an ionic current to or from a first target region interior of the skull; and a transparenchymal channel configured for brain implant entirely beneath the outer layer of the skull and to be associated with the transcranial channel, the transparenchymal channel having a transparenchymal inner lumen adapted to conduct the ionic current to or from a second target region interior of the brain.
 2. The system of claim 1, wherein the transcranial channel further comprises: an inner wall extending between the transcranial channel proximal end and the transcranial channel distal end.
 3. The system of claim 2, wherein the inner wall is formed of an ion permeable material.
 4. The system of claim 1 wherein the transcranial channel further comprises an outer wall formed of a material that is not ion permeable.
 5. The system of claim 1, wherein the transcranial inner lumen is configured to be filled with an ion-permeable substance.
 6. The system of claim 1, wherein the transparenchymal channel is formed of a soft, flexible material and comprises: a transparenchymal channel proximal end designed to be implanted at least partially in an epidural space of the subject's brain between an inner layer of the skull and the dura matter, a transparenchymal channel distal end designed to be oriented towards the second target region; and a wall extending between the transparenchymal channel proximal end and the transparenchymal channel distal end and defining the transparenchymal inner lumen.
 7. The system of claim 6, wherein at least a portion of the soft, flexible material is ion permeable.
 8. The system of claim 6, further comprising one or more stiffening elements located in or around the transparenchymal inner lumen, wherein the stiffening elements are configured to maintain the patency of the transparenchymal inner lumen without compromising the flexibility of the transparenchymal channel.
 9. The system of claim 6, wherein the transparenchymal inner lumen is configured to be filled with an ion-permeable substance.
 10. The system of claim 6, wherein the transparenchymal inner lumen is configured to receive a stylet.
 11. The system of claim 6, wherein the transparenchymal channel further comprises a second lumen independent of and extending generally parallel to the transparenchymal inner lumen, the second lumen configured to receive a stylet.
 12. The system of claim 6, wherein the transparenchymal channel further comprises a collector at the transparenchymal channel proximal end, wherein the collector is configured for implant beneath the inner layer of the skull and defines a proximal portion of the transparenchymal inner lumen having a diameter greater than the diameter of the portion of the transparenchymal inner lumen distal the proximal portion.
 13. The system of claim 6, wherein at least one portion of the transparenchymal channel is designed to contact the second target region.
 14. The system of claim 1, wherein the transparenchymal channel is associated with the transcranial channel by a physical connection such that the transcranial inner lumen and the transparenchymal inner lumen form a continuous conduit.
 15. The system of claim 1, wherein the transparenchymal channel is associated with the transcranial channel by a physical alignment between the transcranial inner lumen and the transparenchymal inner lumen such that the transcranial inner lumen and the transparenchymal inner lumen form a discontinuous conduit.
 16. The system of claim 1, wherein the transcranial inner lumen and the transparenchymal inner lumen form a conduit adapted to facilitate transmission of an ionic current from the brain resulting from electrical activity of the brain.
 17. The system of claim 1, wherein the transcranial inner lumen and the transparenchymal inner lumen form a conduit adapted to transmit charged particles of a biologically-active agent into the intracranial space.
 18. The system of claim 17, wherein the biologically-active agent is selected from the group consisting of: glutamate, acetylcholine, valproate, aspartate, gamma amino butyrate, adrenocorticotropic hormone, cortisol, beta endorphin, and serotonin. 